Structure of a Pancreatic ATP-Sensitive Potassium Channel.

ATP-sensitive potassium channels (KATP) couple intracellular ATP levels with membrane excitability. These channels play crucial roles in many essential physiological processes and have been implicated extensively in a spectrum of metabolic diseases and disorders. To gain insight into the mechanism of KATP, we elucidated the structure of a hetero-octameric pancreatic KATP channel in complex with a non-competitive inhibitor glibenclamide by single-particle cryoelectron microscopy to 5.6-Å resolution. The structure shows that four SUR1 regulatory subunits locate peripherally and dock onto the central Kir6.2 channel tetramer through the SUR1 TMD0-L0 fragment. Glibenclamide-bound SUR1 uses TMD0-L0 fragment to stabilize Kir6.2 channel in a closed conformation. In another structural population, a putative co-purified phosphatidylinositol 4,5-bisphosphate (PIP2) molecule uncouples Kir6.2 from glibenclamide-bound SUR1. These structural observations suggest a molecular mechanism for KATP regulation by anti-diabetic sulfonylurea drugs, intracellular adenosine nucleotide concentrations, and PIP2 lipid.

Structural insights into the ubiquitylation strategy of the oligomeric CRL2FEM1B E3 ubiquitin ligase.

Cullin-RING E3 ubiquitin ligase (CRL) family members play critical roles in numerous biological processes and diseases including cancer and Alzheimer's disease. Oligomerization of CRLs has been reported to be crucial for the regulation of their activities. However, the structural basis for its regulation and mechanism of its oligomerization are not fully known. Here, we present cryo-EM structures of oligomeric CRL2FEM1B in its unneddylated state, neddylated state in complex with BEX2 as well as neddylated state in complex with FNIP1/FLCN. These structures reveal that asymmetric dimerization of N8-CRL2FEM1B is critical for the ubiquitylation of BEX2 while FNIP1/FLCN is ubiquitylated by monomeric CRL2FEM1B. Our data present an example of the asymmetric homo-dimerization of CRL. Taken together, this study sheds light on the ubiquitylation strategy of oligomeric CRL2FEM1B according to substrates with different scales.

Transient states during the annealing of mismatched and bulged oligonucleotides.

Oligonucleotide hybridization is crucial in various biological, prebiotic and nanotechnological processes, including gene regulation, non-enzymatic primer extension and DNA nanodevice assembly. Although extensive research has focused on the thermodynamics and kinetics of nucleic acid hybridization, the behavior of complex mixtures and the outcome of competition for target binding remain less well understood. In this study, we investigate the impact of mismatches and bulges in a 12 bp DNA or RNA duplex on its association (kon) and dissociation (koff) kinetics. We find that such defects have relatively small effects on the association kinetics, while the dissociation kinetics vary in a position-dependent manner by up to 6 orders of magnitude. Building upon this observation, we explored a competition scenario involving multiple oligonucleotides, and observed a transient low specificity of probe hybridization to fully versus partially complementary targets in solution. We characterize these long-lived metastable states and their evolution toward equilibrium, and show that sufficiently long-lived mis-paired duplexes can serve as substrates for prebiotically relevant chemical copying reactions. Our results suggest that transient low accuracy states may spontaneously emerge within all complex nucleic acid systems comprising a large enough number of competing strands, with potential repercussions for gene regulation in the realm of modern biology and the prebiotic preservation of genetic information.

Enhanced nonenzymatic RNA copying with in-situ activation of short oligonucleotides.

The nonenzymatic copying of RNA is thought to have been necessary for the transition between prebiotic chemistry and ribozyme-catalyzed RNA replication in the RNA World. We have previously shown that a potentially prebiotic nucleotide activation pathway based on phospho-Passerini chemistry can lead to the efficient synthesis of 2-aminoimidazole activated mononucleotides when carried out under freeze-thaw cycling conditions. Such activated nucleotides react with each other to form 5'-5' 2-aminoimidazolium bridged dinucleotides, enabling template-directed primer extension to occur within the same reaction mixture. However, mononucleotides linked to oligonucleotides by a 5'-5' 2-aminoimidazolium bridge are superior substrates for nonenzymatic primer extension; their higher intrinsic reactivity and their higher template affinity enable faster template copying at lower substrate concentrations. Here we show that eutectic phase phospho-Passerini chemistry efficiently activates short oligonucleotides and promotes the formation of monomer-bridged-oligonucleotide species during freeze-thaw cycles. We then demonstrate that in-situ generated monomer-bridged-oligonucleotides lead to efficient nonenzymatic template copying in the same reaction mixture. Our demonstration that multiple steps in the pathway from activation chemistry to RNA copying can occur together in a single complex environment simplifies this aspect of the origin of life.

The absence of a prebiotically plausible pathway for the efficient nonenzymatic copying of RNAs remains a major obstacle towards constructing self-replicating protocells that emulate early lifeforms. We demonstrate the activation of short oligonucleotides and the subsequent formation of monomer-bridged-oligonucleotide species, leading to efficient nonenzymatic template copying in the same reaction mixture. Our findings suggest that in-situ activated mixtures of mono- and oligo-nucleotides would significantly outperform mononucleotides in driving the copying of arbitrary RNA sequences. Our demonstration that multiple steps in the pathway from activation chemistry to RNA copying can occur together in a single complex environment simplifies this aspect of the origin of life.

Freeze-thaw cycles enable a prebiotically plausible and continuous pathway from nucleotide activation to nonenzymatic RNA copying.

Nonenzymatic template-directed RNA copying using chemically activated nucleotides is thought to have played a key role in the emergence of genetic information on the early Earth. A longstanding question concerns the number and nature of different environments that might have been necessary to enable all of the steps from nucleotide synthesis to RNA copying. Here we explore three sequential steps from this overall pathway: nucleotide activation, synthesis of imidazolium-bridged dinucleotides, and template-directed RNA copying. We find that all three steps can take place in one reaction mixture undergoing multiple freeze-thaw cycles. Recent experiments have demonstrated a potentially prebiotic methyl isocyanide-based nucleotide activation chemistry. However, the original version of this approach is incompatible with nonenzymatic RNA copying because the high required concentration of the imidazole activating group prevents the accumulation of the essential imidazolium-bridged dinucleotide. Here we report that ice eutectic phase conditions facilitate not only the methyl isocyanide-based activation of ribonucleotide 5'-monophosphates with stoichiometric 2-aminoimidazole, but also the subsequent conversion of these activated mononucleotides into imidazolium-bridged dinucleotides. Furthermore, this one-pot approach is compatible with template-directed RNA copying in the same reaction mixture. Our results suggest that the simple and common environmental fluctuation of freeze-thaw cycles could have played an important role in prebiotic nucleotide activation and nonenzymatic RNA copying.

Diaminopurine in Nonenzymatic RNA Template Copying.

In the RNA World before the emergence of an RNA polymerase, nonenzymatic template copying would have been essential for the transmission of genetic information. However, the products of chemical copying with the canonical nucleotides (A, U, C, and G) are heavily biased toward the incorporation of G and C, which form a more stable base pair than A and U. We therefore asked whether replacing adenine (A) with diaminopurine (D) might lead to more efficient and less biased nonenzymatic template copying by making a stronger version of the A:U pair. As expected, primer extension substrates containing D bound to U in the template more tightly than substrates containing A. However, primer extension with D exhibited elevated reaction rates on a C template, leading to concerns about fidelity. Our crystallographic studies revealed the nature of the D:C mismatch by showing that D can form a wobble-type base pair with C. We then asked whether competition with G would decrease the mismatched primer extension. We performed nonenzymatic primer extension with all four activated nucleotides on randomized RNA templates containing all four letters and used deep sequencing to analyze the products. We found that the DUCG genetic system exhibited a more even product distribution and a lower mismatch frequency than the canonical AUCG system. Furthermore, primer extension is greatly reduced following all mismatches, including the D:C mismatch. Our study suggests that D deserves further attention for its possible role in the RNA World and as a potentially useful component of artificial nonenzymatic RNA replication systems.

Unusual Base Pair between Two 2-Thiouridines and Its Implication for Nonenzymatic RNA Copying.

2-Thiouridine (s2U) is a nucleobase modification that confers enhanced efficiency and fidelity both on modern tRNA codon translation and on nonenzymatic and ribozyme-catalyzed RNA copying. We have discovered an unusual base pair between two 2-thiouridines that stabilizes an RNA duplex to a degree that is comparable to that of a native A:U base pair. High-resolution crystal structures indicate similar base-pairing geometry and stacking interactions in duplexes containing s2U:s2U compared to those with U:U pairs. Notably, the C═O···H-N hydrogen bond in the U:U pair is replaced with a C═S···H-N hydrogen bond in the s2U:s2U base pair. The thermodynamic stability of the s2U:s2U base pair suggested that this self-pairing might lead to an increased error frequency during nonenzymatic RNA copying. However, competition experiments show that s2U:s2U base-pairing induces only a low level of misincorporation during nonenzymatic RNA template copying because the correct A:s2U base pair outcompetes the slightly weaker s2U:s2U base pair. In addition, even if an s2U is incorrectly incorporated, the addition of the next base is greatly hindered. This strong stalling effect would further increase the effective fidelity of nonenzymatic RNA copying with s2U. Our findings suggest that s2U may enhance the rate and extent of nonenzymatic copying with only a minimal cost in fidelity.

Health-Oriented Emission Control Strategy of Energy Utilization and Its Co-CO2 Benefits: A Case Study of the Yangtze River Delta, China.

Reducing air pollutants and CO2 emissions from energy utilization is crucial for achieving the dual objectives of clean air and carbon neutrality in China. Thus, an optimized health-oriented strategy is urgently needed. Herein, by coupling a CO2 and air pollutants emission inventory with response surface models for PM2.5-associated mortality, we shed light on the effectiveness of protecting human health and co-CO2 benefit from reducing fuel-related emissions and generate a health-oriented strategy for the Yangtze River Delta (YRD). Results reveal that oil consumption is the primary contributor to fuel-related PM2.5 pollution and premature deaths in the YRD. Significantly, curtailing fuel consumption in transportation is the most effective measure to alleviate the fuel-related PM2.5 health impact, which also has the greatest cobenefits for CO2 emission reduction on a regional scale. Reducing fuel consumption will achieve substantial health improvements especially in eastern YRD, with nonroad vehicle emission reductions being particularly impactful for health protection, while on-road vehicles present the greatest potential for CO2 reductions. Scenario analysis confirms the importance of mitigating oil consumption in the transportation sector in addressing PM2.5 pollution and climate change.

Spatially and Temporally Differentiated NOx and VOCs Emission Abatement Could Effectively Gain O3-Related Health Benefits.

The increasing level of O3 pollution in China significantly exacerbates the long-term O3 health damage, and an optimized health-oriented strategy for NOx and VOCs emission abatement is needed. Here, we developed an integrated evaluation and optimization system for the O3 control strategy by merging a response surface model for the O3-related mortality and an optimization module. Applying this system to the Yangtze River Delta (YRD), we evaluated driving factors for mortality changes from 2013 to 2017, quantified spatial and temporal O3-related mortality responses to precursor emission abatement, and optimized a health-oriented control strategy. Results indicate that insufficient NOx emission abatement combined with deficient VOCs control from 2013 to 2017 aggravated O3-related mortality, particularly during spring and autumn. Northern YRD should promote VOCs control due to higher VOC-limited characteristics, whereas fastening NOx emission abatement is more favorable in southern YRD. Moreover, promotion of NOx mitigation in late spring and summer and facilitating VOCs control in spring and autumn could further reduce O3-related mortality by nearly 10% compared to the control strategy without seasonal differences. These findings highlight that a spatially and temporally differentiated NOx and VOCs emission control strategy could gain more O3-related health benefits, offering valuable insights to regions with severe ozone pollution all over the world.

Air Quality, Health, and Equity Benefits of Carbon Neutrality and Clean Air Pathways in China.

In the pursuit of carbon neutrality, China's 2060 targets have been largely anchored in reducing greenhouse gas emissions, with less emphasis on the consequential benefits for air quality and public health. This study pivots to this critical nexus, exploring how China's carbon neutrality aligns with the World Health Organization's air quality guidelines (WHO AQG) regarding fine particulate matter (PM2.5) exposure. Coupling a technology-rich integrated assessment model, an emission-concentration response surface model, and exposure and health assessment, we find that decarbonization reduces sulfur dioxide (SO2), nitrogen oxides (NOx), and PM2.5 emissions by more than 90%; reduces nonmethane volatile organic compounds (NMVOCs) by more than 50%; and simultaneously reduces the disparities across regions. Critically, our analysis reveals that further targeted reductions in air pollutants, notably NH3 and non-energy-related NMVOCs, could bring most Chinese cities into attainment of WHO AQG for PM2.5 5 to 10 years earlier than the pathway focused solely on carbon neutrality. Thus, the integration of air pollution control measures into carbon neutrality strategies will present a significant opportunity for China to attain health and environmental equality.

Kinetic explanations for the sequence biases observed in the nonenzymatic copying of RNA templates.

The identification of nonenzymatic pathways for nucleic acid replication is a key challenge in understanding the origin of life. We have previously shown that nonenzymatic RNA primer extension using 2-aminoimidazole (2AI) activated nucleotides occurs primarily through an imidazolium-bridged dinucleotide intermediate. The reactive nature and preorganized structure of the intermediate increase the efficiency of primer extension but remain insufficient to drive extensive copying of RNA templates containing all four canonical nucleotides. To understand the factors that limit RNA copying, we synthesized all ten 2AI-bridged dinucleotide intermediates and measured the kinetics of primer extension in a model system. The affinities of the ten dinucleotides for the primer/template/helper complexes vary by over 7,000-fold, consistent with nearest neighbor energetic predictions. Surprisingly, the reaction rates at saturating intermediate concentrations still vary by over 15-fold, with the most weakly binding dinucleotides exhibiting a lower maximal reaction rate. Certain noncanonical nucleotides can decrease sequence dependent differences in affinity and primer extension rate, while monomers bridged to short oligonucleotides exhibit enhanced binding and reaction rates. We suggest that more uniform binding and reactivity of imidazolium-bridged intermediates may lead to the ability to copy arbitrary template sequences under prebiotically plausible conditions.

Experimental Tests of the Virtual Circular Genome Model for Nonenzymatic RNA Replication.

The virtual circular genome (VCG) model was proposed as a means of going beyond template copying to indefinite cycles of nonenzymatic RNA replication during the origin of life. In the VCG model, the protocellular genome is a collection of short oligonucleotides that map to both strands of a virtual circular sequence. Replication is driven by templated nonenzymatic primer extensions on a subset of kinetically trapped partially base-paired configurations, followed by the shuffling of these configurations to enable continued oligonucleotide elongation. Here, we describe initial experimental studies of the feasibility of the VCG model for replication. We designed a small 12-nucleotide model VCG and synthesized all 247 oligonucleotides of lengths 2 to 12 corresponding to this genome. We experimentally monitored the fate of individual labeled primers in the pool of VCG oligonucleotides following the addition of activated nucleotides and investigated the effect of factors such as oligonucleotide length, concentration, composition, and temperature on the extent of primer extension. We observe a surprisingly prolonged equilibration process in the VCG system that enables a considerable extent of reaction. We find that environmental fluctuations would be essential for continuous templated extension of the entire VCG system since the shortest oligonucleotides can only bind to templates at low temperatures, while the longest oligonucleotides require high-temperature spikes to escape from inactive configurations. Finally, we demonstrate that primer extension is significantly enhanced when the mix of VCG oligonucleotides is preactivated. We discuss the necessity of ongoing in situ activation chemistry for continuous and accurate VCG replication.

The virtual circular genome model for primordial RNA replication.

We propose a model for the replication of primordial protocell genomes that builds upon recent advances in the nonenzymatic copying of RNA. We suggest that the original genomes consisted of collections of oligonucleotides beginning and ending at all possible positions on both strands of one or more virtual circular sequences. Replication is driven by feeding with activated monomers and by the activation of monomers and oligonucleotides in situ. A fraction of the annealed configurations of the protocellular oligonucleotides would allow for template-directed oligonucleotide growth by primer extension or ligation. Rearrangements of these annealed configurations, driven either by environmental fluctuations or occurring spontaneously, would allow for continued oligonucleotide elongation. Assuming that shorter oligonucleotides were more abundant than longer ones, replication of the entire genome could occur by the growth of all oligonucleotides by as little as one nucleotide on average. We consider possible scenarios that could have given rise to such protocell genomes, as well as potential routes to the emergence of catalytically active ribozymes and thus the more complex cells of the RNA World.

Extreme Emission Reduction Requirements for China to Achieve World Health Organization Global Air Quality Guidelines.

A big gap exists between current air quality in China and the World Health Organization (WHO) global air quality guidelines (AQG) released in 2021. Previous studies on air pollution control have focused on emission reduction demand in China but ignored the influence of transboundary pollution, which has been proven to have a significant impact on air quality in China. Here, we develop an emission-concentration response surface model coupled with transboundary pollution to quantify the emission reduction demand for China to achieve WHO AQG. China cannot achieve WHO AQG by its own emission reduction for high transboundary pollution of both PM2.5 and O3. Reducing transboundary pollution will loosen the reduction demand for NH3 and VOCs emissions in China. However, to meet 10 µg·m-3 for PM2.5 and 60 µg·m-3 for peak season O3, China still needs to reduce its emissions of SO2, NOx, NH3, VOCs, and primary PM2.5 by more than 95, 95, 76, 62, and 96% respectively, on the basis of 2015. We highlight that both extreme emission reduction in China and great efforts in addressing transboundary air pollution are crucial to reach WHO AQG.

Mismatched Social Welfare Allocation and PM2.5-Related Health Damage along Value Chains within China.

Value chains have played a critical part in the growth. However, the fairness of the social welfare allocation along the value chain is largely underinvestigated, especially when considering the harmful environmental and health effects associated with the production processes. We used fine-scale profiling to analyze the social welfare allocation along China's domestic value chain within the context of environmental and health effects and investigated the underlying mechanisms. Our results suggested that the top 10% regions in the value chain obtained 2.9 times more social income and 2.1 times more job opportunities than the average, with much lower health damage. Further inspection showed a significant contribution of the "siphon effect"─major resource providers suffer the most in terms of localized health damage along with insufficient social welfare for compensation. We found that inter-region atmosphere transport results in redistribution for 53% health damages, which decreases the welfare-damage mismatch at "suffering" regions but also causes serious health damage to more than half of regions and populations in total. Specifically, around 10% of regions have lower social welfare and also experienced a significant increase in health damage caused by atmospheric transport. These results highlighted the necessity of a value chain-oriented, quantitative compensation-driven policy.

Sources of Organic Aerosol in China from 2005 to 2019: A Modeling Analysis.

Organic aerosol (OA) is a key component of fine particulate matter (PM2.5) and affects the human health and leads to climate change. With strict control measures for air pollutants during the last decade, the OA concentration in China declined slowly, while its sources remain unclear. In this study, we simulate the primary OA (POA) and secondary OA (SOA) concentrations from 2005 to 2019 with a state-of-the-art air quality model, Community Multiscale Air Quality (CMAQ, version 5.3.2) coupled with a Two-Dimensional Volatility Basis Set (2D-VBS) module, and a long-term emission inventory of full-volatility organic compounds in China and conduct source apportionment and sensitivity analysis. The simulation results show that, from 2005 to 2019, the OA concentration in China decreased from 24.0 to 12.8 µg/m3 with most of the reduction from POA. The OA pollution from residential biomass burning declined 75% from 2005 to 2019, while it is still the major OA source in China. OA pollution from VCP increased by more than 2-fold and became the largest SOA source in China. From 2014 to 2019, the NOx control in China slightly offset the decrease of SOA concentration due to elevated oxidation capacity.

Competition between bridged dinucleotides and activated mononucleotides determines the error frequency of nonenzymatic RNA primer extension.

Nonenzymatic copying of RNA templates with activated nucleotides is a useful model for studying the emergence of heredity at the origin of life. Previous experiments with defined-sequence templates have pointed to the poor fidelity of primer extension as a major problem. Here we examine the origin of mismatches during primer extension on random templates in the simultaneous presence of all four 2-aminoimidazole-activated nucleotides. Using a deep sequencing approach that reports on millions of individual template-product pairs, we are able to examine correct and incorrect polymerization as a function of sequence context. We have previously shown that the predominant pathway for primer extension involves reaction with imidazolium-bridged dinucleotides, which form spontaneously by the reaction of two mononucleotides with each other. We now show that the sequences of correctly paired products reveal patterns that are expected from the bridged dinucleotide mechanism, whereas those associated with mismatches are consistent with direct reaction of the primer with activated mononucleotides. Increasing the ratio of bridged dinucleotides to activated mononucleotides, either by using purified components or by using isocyanide-based activation chemistry, reduces the error frequency. Our results point to testable strategies for the accurate nonenzymatic copying of arbitrary RNA sequences.

The quest for improved air quality may push China to continue its CO2 reduction beyond the Paris Commitment.

China is challenged with the simultaneous goals of improving air quality and mitigating climate change. The "Beautiful China" strategy, launched by the Chinese government in 2020, requires that all cities in China attain 35 µg/m3 or below for annual mean concentration of PM2.5 (particulate matter with aerodynamic diameter less than 2.5 µm) by 2035. Meanwhile, China adopts a portfolio of low-carbon policies to meet its Nationally Determined Contribution (NDC) pledged in the Paris Agreement. Previous studies demonstrated the cobenefits to air pollution reduction from implementing low-carbon energy policies. Pathways for China to achieve dual targets of both air quality and CO2 mitigation, however, have not been comprehensively explored. Here, we couple an integrated assessment model and an air quality model to evaluate air quality in China through 2035 under the NDC scenario and an alternative scenario (Co-Benefit Energy [CBE]) with enhanced low-carbon policies. Results indicate that some Chinese cities cannot meet the PM2.5 target under the NDC scenario by 2035, even with the strictest end-of-pipe controls. Achieving the air quality target would require further reduction in emissions of multiple air pollutants by 6 to 32%, driving additional 22% reduction in CO2 emissions relative to the NDC scenario. Results show that the incremental health benefit from improved air quality of CBE exceeds 8 times the additional costs of CO2 mitigation, attributed particularly to the cost-effective reduction in household PM2.5 exposure. The additional low-carbon energy polices required for China's air quality targets would lay an important foundation for its deep decarbonization aligned with the 2 °C global temperature target.

Synergetic PM2.5 and O3 control strategy for the Yangtze River Delta, China.

PM2.5 concentrations have dramatically reduced in key regions of China during the period 2013-2017, while O3 has increased. Hence there is an urgent demand to develop a synergetic regional PM2.5 and O3 control strategy. This study develops an emission-to-concentration response surface model and proposes a synergetic pathway for PM2.5 and O3 control in the Yangtze River Delta (YRD) based on the framework of the Air Benefit and Cost and Attainment Assessment System (ABaCAS). Results suggest that the regional emissions of NOx, SO2, NH3, VOCs (volatile organic compounds) and primary PM2.5 should be reduced by 18%, 23%, 14%, 17% and 33% compared with 2017 to achieve 25% and 5% decreases of PM2.5 and O3 in 2025, and that the emission reduction ratios will need to be 50%, 26%, 28%, 28% and 55% to attain the National Ambient Air Quality Standard. To effectively reduce the O3 pollution in the central and eastern YRD, VOCs controls need to be strengthened to reduce O3 by 5%, and then NOx reduction should be accelerated for air quality attainment. Meanwhile, control of primary PM2.5 emissions shall be prioritized to address the severe PM2.5 pollution in the northern YRD. For most cities in the YRD, the VOCs emission reduction ratio should be higher than that for NOx in Spring and Autumn. NOx control should be increased in summer rather than winter when a strong VOC-limited regime occurs. Besides, regarding the emission control of industrial processes, on-road vehicle and residential sources shall be prioritized and the joint control area should be enlarged to include Shandong, Jiangxi and Hubei Province for effective O3 control.

The Emerging Structural Pharmacology of ATP-Sensitive Potassium Channels.

ATP-sensitive potassium channels (KATP) are energy sensors that participate in a range of physiologic processes. These channels are also clinically validated drug targets. For decades, KATP inhibitors have been prescribed for diabetes and KATP activators have been used for the treatment of hypoglycemia, hypertension, and hair loss. In this Emerging Concepts article, we highlight our current knowledge about the drug binding modes observed using cryogenic electron microscopy techniques. The inhibitors and activators bind to two distinct sites in the transmembrane domain of the sulfonylurea receptor (SUR) subunit. We also discuss the possible mechanism of how these drugs allosterically modulate the dimerization of SUR nucleotide-binding domains (NBDs) and thus KATP channel activity. SIGNIFICANCE STATEMENT: ATP-sensitive potassium channels (KATP) are fundamental to energy homeostasis, and they participate in many vital physiological processes. KATP channels are important drug targets. Both KATP inhibitors (insulin secretagogues) and KATP activators are broadly used clinically for the treatment of related diseases. Recent cryogenic electron microscopy studies allow us to understand the emerging concept of KATP structural pharmacology.