Architecture and membrane interactions of the EGF receptor.

Dimerization-driven activation of the intracellular kinase domains of the epidermal growth factor receptor (EGFR) upon extracellular ligand binding is crucial to cellular pathways regulating proliferation, migration, and differentiation. Inactive EGFR can exist as both monomers and dimers, suggesting that the mechanism regulating EGFR activity may be subtle. The membrane itself may play a role but creates substantial difficulties for structural studies. Our molecular dynamics simulations of membrane-embedded EGFR suggest that, in ligand-bound dimers, the extracellular domains assume conformations favoring dimerization of the transmembrane helices near their N termini, dimerization of the juxtamembrane segments, and formation of asymmetric (active) kinase dimers. In ligand-free dimers, by holding apart the N termini of the transmembrane helices, the extracellular domains instead favor C-terminal dimerization of the transmembrane helices, juxtamembrane segment dissociation and membrane burial, and formation of symmetric (inactive) kinase dimers. Electrostatic interactions of EGFR's intracellular module with the membrane are critical in maintaining this coupling.

Conformational coupling across the plasma membrane in activation of the EGF receptor.

How the epidermal growth factor receptor (EGFR) activates is incompletely understood. The intracellular portion of the receptor is intrinsically active in solution, and to study its regulation, we measured autophosphorylation as a function of EGFR surface density in cells. Without EGF, intact EGFR escapes inhibition only at high surface densities. Although the transmembrane helix and the intracellular module together suffice for constitutive activity even at low densities, the intracellular module is inactivated when tethered on its own to the plasma membrane, and fluorescence cross-correlation shows that it fails to dimerize. NMR and functional data indicate that activation requires an N-terminal interaction between the transmembrane helices, which promotes an antiparallel interaction between juxtamembrane segments and release of inhibition by the membrane. We conclude that EGF binding removes steric constraints in the extracellular module, promoting activation through N-terminal association of the transmembrane helices.

The dynamic process of ß(2)-adrenergic receptor activation.

G-protein-coupled receptors (GPCRs) can modulate diverse signaling pathways, often in a ligand-specific manner. The full range of functionally relevant GPCR conformations is poorly understood. Here, we use NMR spectroscopy to characterize the conformational dynamics of the transmembrane core of the ß(2)-adrenergic receptor (ß(2)AR), a prototypical GPCR. We labeled ß(2)AR with (13)CH(3)ε-methionine and obtained HSQC spectra of unliganded receptor as well as receptor bound to an inverse agonist, an agonist, and a G-protein-mimetic nanobody. These studies provide evidence for conformational states not observed in crystal structures, as well as substantial conformational heterogeneity in agonist- and inverse-agonist-bound preparations. They also show that for ß(2)AR, unlike rhodopsin, an agonist alone does not stabilize a fully active conformation, suggesting that the conformational link between the agonist-binding pocket and the G-protein-coupling surface is not rigid. The observed heterogeneity may be important for ß(2)AR's ability to engage multiple signaling and regulatory proteins.

Oncogenic mutations counteract intrinsic disorder in the EGFR kinase and promote receptor dimerization.

The mutation and overexpression of the epidermal growth factor receptor (EGFR) are associated with the development of a variety of cancers, making this prototypical dimerization-activated receptor tyrosine kinase a prominent target of cancer drugs. Using long-timescale molecular dynamics simulations, we find that the N lobe dimerization interface of the wild-type EGFR kinase domain is intrinsically disordered and that it becomes ordered only upon dimerization. Our simulations suggest, moreover, that some cancer-linked mutations distal to the dimerization interface, particularly the widespread L834R mutation (also referred to as L858R), facilitate EGFR dimerization by suppressing this local disorder. Corroborating these findings, our biophysical experiments and kinase enzymatic assays indicate that the L834R mutation causes abnormally high activity primarily by promoting EGFR dimerization rather than by allowing activation without dimerization. We also find that phosphorylation of EGFR kinase domain at Tyr845 may suppress the intrinsic disorder, suggesting a molecular mechanism for autonomous EGFR signaling.

Discovery of lirafugratinib (RLY-4008), a highly selective irreversible small-molecule inhibitor of FGFR2.

Fibroblast growth factor receptor (FGFR) kinase inhibitors have been shown to be effective in the treatment of intrahepatic cholangiocarcinoma and other advanced solid tumors harboring FGFR2 alterations, but the toxicity of these drugs frequently leads to dose reduction or interruption of treatment such that maximum efficacy cannot be achieved. The most common adverse effects are hyperphosphatemia caused by FGFR1 inhibition and diarrhea due to FGFR4 inhibition, as current therapies are not selective among the FGFRs. Designing selective inhibitors has proved difficult with conventional approaches because the orthosteric sites of FGFR family members are observed to be highly similar in X-ray structures. In this study, aided by analysis of protein dynamics, we designed a selective, covalent FGFR2 inhibitor. In a key initial step, analysis of long-timescale molecular dynamics simulations of the FGFR1 and FGFR2 kinase domains allowed us to identify differential motion in their P-loops, which are located adjacent to the orthosteric site. Using this insight, we were able to design orthosteric binders that selectively and covalently engage the P-loop of FGFR2. Our drug discovery efforts culminated in the development of lirafugratinib (RLY-4008), a covalent inhibitor of FGFR2 that shows substantial selectivity over FGFR1 (~250-fold) and FGFR4 (~5,000-fold) in vitro, causes tumor regression in multiple FGFR2-altered human xenograft models, and was recently demonstrated to be efficacious in the clinic at doses that do not induce clinically significant hyperphosphatemia or diarrhea.

Selective Inhibition of NaV1.8 with VX-548 for Acute Pain.

BACKGROUND: The NaV1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of NaV1.8, on control of acute pain is being studied. METHODS: After establishing the selectivity of VX-548 for NaV1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo. RESULTS: A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548. CONCLUSIONS: As compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.).

The (mis)use of ChatGPT in science and education: Turing, Djerassi, "athletics" & ethics.

ChatGPT is an amazing advance in technology, but it poses problems for teachers in universities and schools. How should use of ChatGPT by students be dealt with?

Point of care testing for hepatitis C in the priority settings of mental health, prisons and drug & alcohol facilities - the PROMPt Study.

BACKGROUND: A barrier to hepatitis C virus (HCV) cure is conventional testing. The aim of this study was to evaluate the effect of HCV antibody and RNA point-of-care-testing (POCT) on testing rates, linkage to care, treatment and acceptability of testing in three priority settings in Australia. METHODS: Participants were enrolled in an interventional cohort study at a reception prison, inpatient mental health service (MHS), and inpatient alcohol and other drug (AOD) unit-between October 2020 and December 2021. HCV POCT was performed using SD Bioline HCV antibody fingerstick test and a reflexive Xpert® HCV Viral Load Fingerstick test using capillary blood samples. A retrospective audit of HCV testing and treatment data was performed at each site for the preceding 12-month period to generate a historical control. RESULTS: 1,549 participants received a HCV antibody test with 17% (264/1,549) receiving a positive result, of which 21% (55/264) tested HCV RNA positive. Across all settings the rate of testing per year significantly increased between the historical controls and the study intervention period by three-fold (RR:2.57 95% CI: 2.32, 2.85) for HCV antibody testing and four-fold (RR:1.62; 95% CI:1.31, 2.01) for RNA testing. Treatment uptake was higher during the POCT intervention (86%, 47/55; P=0.010) compared to the historical controls (61%, 27/44). CONCLUSIONS: This study demonstrated across three settings that the use of HCV antibody and RNA POCT increased testing rates, treatment uptake linkage to care. The testing model was highly acceptable for most participants. CLINICAL TRIAL REGISTRATION: ACTRN-12621001578897.

Genetic architecture of disease resistance and tolerance in Douglas-fir trees.

Understanding the genetic basis of how plants defend against pathogens is important to monitor and maintain resilient tree populations. Swiss needle cast (SNC) and Rhabdocline needle cast (RNC) epidemics are responsible for major damage of forest ecosystems in North America. Here we investigate the genetic architecture of tolerance and resistance to needle cast diseases in Douglas-fir (Pseudotsuga menziesii) caused by two fungal pathogens: SNC caused by Nothophaeocryptopus gaeumannii, and RNC caused by Rhabdocline pseudotsugae. We performed case-control genome-wide association analyses and found disease resistance and tolerance in Douglas-fir to be polygenic and under strong selection. We show that stomatal regulation as well as ethylene and jasmonic acid pathways are important for resisting SNC infection, and secondary metabolite pathways play a role in tolerating SNC once the plant is infected. We identify a major transcriptional regulator of plant defense, ERF1, as the top candidate for RNC resistance. Our findings shed light on the highly polygenic architectures underlying fungal disease resistance and tolerance and have important implications for forestry and conservation as the climate changes.

Mechanism of NMDA receptor channel block by MK-801 and memantine.

The NMDA (N-methyl-D-aspartate) receptor transduces the binding of glutamate and glycine, coupling it to the opening of a calcium-permeable ion channel 1 . Owing to the lack of high-resolution structural studies of the NMDA receptor, the mechanism by which ion-channel blockers occlude ion permeation is not well understood. Here we show that removal of the amino-terminal domains from the GluN1-GluN2B NMDA receptor yields a functional receptor and crystals with good diffraction properties, allowing us to map the binding site of the NMDA receptor blocker, MK-801. This crystal structure, together with long-timescale molecular dynamics simulations, shows how MK-801 and memantine (a drug approved for the treatment of Alzheimer's disease) bind within the vestibule of the ion channel, promote closure of the ion channel gate and lodge between the M3-helix-bundle crossing and the M2-pore loops, physically blocking ion permeation.

Long-term prediction of the effects of climate change on indoor climate and air quality.

Limiting the negative impact of climate change on nature and humans is one of the most pressing issues of the 21st century. Meanwhile, people in modern society spend most of the day indoors. It is therefore surprising that comparatively little attention has been paid to indoor human exposure in relation to climate change. Heat action plans have now been designed in many regions to protect people from thermal stress in their private homes and in public buildings. However, in order to be able to plan effectively for the future, reliable information is required about the long-term effects of climate change on indoor air quality and climate. The Indoor Air Quality Climate Change (IAQCC) model is an expediant tool for estimating the influence of climate change on indoor air quality. The model follows a holistic approach in which building physics, emissions, chemical reactions, mold growth and exposure are combined with the fundamental parameters of temperature and humidity. The features of the model have already been presented in an earlier publication, and it is now used for the expected climatic conditions in Central Europe, taking into account various shared socioeconomic pathway (SSP) scenarios up to the year 2100. For the test house examined in this study, the concentrations of pollutants in the indoor air will continue to rise. At the same time, the risk of mold growth also increases (the mold index rose from 0 to 4 in the worst case for very sensitive material). The biggest problem, however, is protection against heat and humidity. Massive structural improvements are needed here, including insulation, ventilation, and direct sun protection. Otherwise, the occupants will be exposed to increasing thermal discomfort, which can also lead to severe heat stress indoors.

Structural basis for backtracking by the SARS-CoV-2 replication-transcription complex.

Backtracking, the reverse motion of the transcriptase enzyme on the nucleic acid template, is a universal regulatory feature of transcription in cellular organisms but its role in viruses is not established. Here we present evidence that backtracking extends into the viral realm, where backtracking by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) may aid viral transcription and replication. Structures of SARS-CoV-2 RdRp bound to the essential nsp13 helicase and RNA suggested the helicase facilitates backtracking. We use cryo-electron microscopy, RNA-protein cross-linking, and unbiased molecular dynamics simulations to characterize SARS-CoV-2 RdRp backtracking. The results establish that the single-stranded 3' segment of the product RNA generated by backtracking extrudes through the RdRp nucleoside triphosphate (NTP) entry tunnel, that a mismatched nucleotide at the product RNA 3' end frays and enters the NTP entry tunnel to initiate backtracking, and that nsp13 stimulates RdRp backtracking. Backtracking may aid proofreading, a crucial process for SARS-CoV-2 resistance against antivirals.

Integrating ethics in AI development: a qualitative study.

BACKGROUND: While the theoretical benefits and harms of Artificial Intelligence (AI) have been widely discussed in academic literature, empirical evidence remains elusive regarding the practical ethical challenges of developing AI for healthcare. Bridging the gap between theory and practice is an essential step in understanding how to ethically align AI for healthcare. Therefore, this research examines the concerns and challenges perceived by experts in developing ethical AI that addresses the healthcare context and needs. METHODS: We conducted semi-structured interviews with 41 AI experts and analyzed the data using reflective thematic analysis. RESULTS: We developed three themes that expressed the considerations perceived by experts as essential for ensuring AI aligns with ethical practices within healthcare. The first theme explores the ethical significance of introducing AI with a clear and purposeful objective. The second theme focuses on how experts are concerned about the tension that exists between economic incentives and the importance of prioritizing the interests of doctors and patients. The third theme illustrates the need to develop context-sensitive AI for healthcare that is informed by its underlying theoretical foundations. CONCLUSIONS: The three themes collectively emphasized that beyond being innovative, AI must genuinely benefit healthcare and its stakeholders, meaning AI also aligns with intricate and context-specific healthcare practices. Our findings signal that instead of narrow product-specific AI guidance, ethical AI development may need a systemic, proactive perspective that includes the ethical considerations (objectives, actors, and context) and focuses on healthcare applications. Ethically developing AI involves a complex interplay between AI, ethics, healthcare, and multiple stakeholders.

AI Through Ethical Lenses: A Discourse Analysis of Guidelines for AI in Healthcare.

While the technologies that enable Artificial Intelligence (AI) continue to advance rapidly, there are increasing promises regarding AI's beneficial outputs and concerns about the challenges of human-computer interaction in healthcare. To address these concerns, institutions have increasingly resorted to publishing AI guidelines for healthcare, aiming to align AI with ethical practices. However, guidelines as a form of written language can be analyzed to recognize the reciprocal links between its textual communication and underlying societal ideas. From this perspective, we conducted a discourse analysis to understand how these guidelines construct, articulate, and frame ethics for AI in healthcare. We included eight guidelines and identified three prevalent and interwoven discourses: (1) AI is unavoidable and desirable; (2) AI needs to be guided with (some forms of) principles (3) trust in AI is instrumental and primary. These discourses signal an over-spillage of technical ideals to AI ethics, such as over-optimism and resulting hyper-criticism. This research provides insights into the underlying ideas present in AI guidelines and how guidelines influence the practice and alignment of AI with ethical, legal, and societal values expected to shape AI in healthcare.

Natural killer cell subset count and antigen-stimulated activation in response to exhaustive running following adaptation to a ketogenic diet.

NEW FINDINGS: What is the central question of this study? Does a ketogenic diet (KD) modulate circulating counts of natural killer (NK) cells, including CD56bright and CD56dim subsets, and their ability to activate (CD69 expression) following in vitro antigen stimulation in response to exhaustive moderate-intensity exercise? What is the main finding and its importance? The KD amplified the biphasic exercise-induced NK cell response due to a greater mobilisation of the cytotoxic CD56dim subset but did not alter NK cell CD69 expression. The KD appears to modulate exercise-induced circulating NK cell mobilisation and egress, but not antigen-stimulated circulating NK cell activation. ABSTRACT: We investigated the effect of a 31-day ketogenic diet (KD) compared with a habitual, carbohydrate (CHO)-based diet on total circulating natural killer (NK) CD3- CD56+ , dim and bright subset count, and antigen-stimulated CD3- CD56+ cell activation (CD69+ ) in response to exhaustive running. In a randomised, repeated-measures, cross-over study, eight trained, male endurance athletes ingested a 31-day low-CHO KD or their habitual diet (HD). On day 31, participants ran to exhaustion at 70% V ̇ O 2 max $\dot{V}_{{\rm{O}}_{2}{\rm{max}}}$ (∼3.5-4 h, ∼45-50 km). A low-CHO (<10 g) meal was ingested prior to the KD trial, with fat ingested during exercise. A high-CHO (2 g kg-1 ) meal was ingested prior to the HD trial, with CHO (∼55 g h-1 ) ingested during exercise. Venous blood samples were collected at pre-exercise, post-exercise and 1 h post-exercise. The KD amplified the classical exercise-induced biphasic CD3- CD56+ cell response by increasing the post-exercise counts (P = 0.0004), which appeared to be underpinned by the cytotoxic CD3- CD56dim subset (main effect of time point, P < 0.0001). The KD had no effect on NK cells' expression of CD69 or their geometric mean fluorescence intensity of CD69 expression, either for unstimulated or for antigen-stimulated NK cells (all P > 0.05). In conclusion, adaptation to a KD may alter the number of circulating NK cells but not their ability to activate to an antigenic challenge.

The effect of a 2 week ketogenic diet, versus a carbohydrate-based diet, on cognitive performance, mood and subjective sleepiness during 36 h of extended wakefulness in military personnel: An exploratory study.

Extended wakefulness, or sleep deprivation, impairs cognitive performance and brain glucose metabolism. A ketogenic diet (KD) provides an alternative fuel source, ketone bodies, that could elicit a metabolic benefit during sleep deprivation. A randomised, cross-over trial was conducted with seven male military personnel. Participants ingested an iso-energetic ketogenic diet or carbohydrate-based diet for 14 days, immediately followed by 36 h of extended wakefulness and separated by a 12 day washout. Cognitive performance, mood, subjective sleepiness, capillary blood glucose, and D-ß-hydroxybutyrate concentrations were measured every 2 h during extended wakefulness. Linear mixed models were used to analyse data. D-ß-hydroxybutyrate was higher (p < 0.001) and glucose was lower (p < 0.01) on the KD compared with the carbohydrate-based diet. The KD improved psychomotor vigilance task performance (number of lapses, mean reciprocal response time, mean fastest 10% response time (RT), and mean slowest 10% RT; all p < 0.05), running memory continuous performance test performance (RT and number of correct responses per minute; both p < 0.01), and vigour, fatigue, and sleepiness (all, p ≤ 0.001) compared with the carbohydrate-based diet. In conclusion, a KD demonstrated beneficial effects on cognitive performance, mood, and sleepiness during 36 h of extended wakefulness compared with a carbohydrate-based diet.

How does a small molecule bind at a cryptic binding site?

Protein-protein interactions (PPIs) are ubiquitous biomolecular processes that are central to virtually all aspects of cellular function. Identifying small molecules that modulate specific disease-related PPIs is a strategy with enormous promise for drug discovery. The design of drugs to disrupt PPIs is challenging, however, because many potential drug-binding sites at PPI interfaces are "cryptic": When unoccupied by a ligand, cryptic sites are often flat and featureless, and thus not readily recognizable in crystal structures, with the geometric and chemical characteristics of typical small-molecule binding sites only emerging upon ligand binding. The rational design of small molecules to inhibit specific PPIs would benefit from a better understanding of how such molecules bind at PPI interfaces. To this end, we have conducted unbiased, all-atom MD simulations of the binding of four small-molecule inhibitors (SP4206 and three SP4206 analogs) to interleukin 2 (IL2)-which performs its function by forming a PPI with its receptor-without incorporating any prior structural information about the ligands' binding. In multiple binding events, a small molecule settled into a stable binding pose at the PPI interface of IL2, resulting in a protein-small-molecule binding site and pose virtually identical to that observed in an existing crystal structure of the IL2-SP4206 complex. Binding of the small molecule stabilized the IL2 binding groove, which when the small molecule was not bound emerged only transiently and incompletely. Moreover, free energy perturbation (FEP) calculations successfully distinguished between the native and non-native IL2-small-molecule binding poses found in the simulations, suggesting that binding simulations in combination with FEP may provide an effective tool for identifying cryptic binding sites and determining the binding poses of small molecules designed to disrupt PPI interfaces by binding to such sites.

Midterm Outcomes of Primary and Secondary Use of an Endoanchor System for Thoracic and Abdominal Aortic Endovascular Aortic Repair.

PURPOSE: To assess the safety, technical success, and midterm outcomes of endoanchor (Heli-FX, Medtronic, Santa Rosa, California) deployment in thoracic endovascular aortic repair (TEVAR) or abdominal endovascular aortic repair (EVAR). MATERIALS AND METHODS: This single-institution, retrospective study of all endoanchor procedures was performed from February 1, 2017 to March 30, 2021. All procedures were performed percutaneously by interventional radiologists. Clinical information and outcome data were retrieved from electronic medical records. Fifty patients (14% females, n = 7; 86% males, n = 43; median age, 79 years [range, 56-93 years]) underwent Endoanchor procedures, with 349 Endoanchors implanted; 33 procedures were primary deployments (at initial stent deployment) and 17 were secondary deployments (previous stent deployment). For the primary group (4 TEVARs and 29 EVARs), indications were prophylactic (n = 30), hostile neck (n = 28), hostile distal landing zone (n = 2), and intraprocedural type 1a endoleaks (n = 3). For the secondary group (4 TEVARs and 13 EVARs), indications were graft migration (n = 8), seal zone expansion without proven endoleak (n = 7) (proximal [n = 4] or distal seal [n = 3]), and proven type 1a endoleak (n = 2). RESULTS: Median number of endoanchors deployed per procedure was 7 (range, 3-10). Median time to deploy endoanchors was 22 minutes (range, 8-46 minutes). The technical success rate of Endoanchor was 99.7% (348/349). The 30-day mortality rate was 0%. The overall adverse event rate was 6% (n = 3). Reinterventions were performed in 12% of patients (n = 6). Median follow-up was 38 months (range, 2-71 months). Overall survival at 1 and 3 years was 95% and 85%, respectively. Overall freedom from type 1a endoleak at 1 and 3 years was 96% and 93%, respectively. CONCLUSIONS: Endoanchor procedures are safe with excellent technical success rate and good midterm clinical outcomes.

Chemical data evaluation: general considerations and approaches for IUPAC projects and the chemistry community (IUPAC Technical Report).

The International Union of Pure and Applied Chemistry (IUPAC) has a long tradition of supporting the compilation of chemical data and their evaluation through direct projects, nomenclature and terminology work, and partnerships with international scientific bodies, government agencies and other organizations. The IUPAC Interdivisional Subcommittee on Critical Evaluation of Data (ISCED) has been established to provide guidance on issues related to the evaluation of chemical data. In this first report we define the general principles of the evaluation of scientific data and describe best practices and approaches to data evaluation in chemistry.

A Conserved Local Structural Motif Controls the Kinetics of PTP1B Catalysis.

Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of the insulin and leptin signaling pathways, making it a highly attractive target for the treatment of type II diabetes. For PTP1B to perform its enzymatic function, a loop referred to as the "WPD loop" must transition between open (catalytically incompetent) and closed (catalytically competent) conformations, which have both been resolved by X-ray crystallography. Although prior studies have established this transition as the rate-limiting step for catalysis, the transition mechanism for PTP1B and other PTPs has been unclear. Here we present an atomically detailed model of WPD loop transitions in PTP1B based on unbiased, long-timescale molecular dynamics simulations and weighted ensemble simulations. We found that a specific WPD loop region─the PDFG motif─acted as the key conformational switch, with structural changes to the motif being necessary and sufficient for transitions between long-lived open and closed states of the loop. Simulations starting from the closed state repeatedly visited open states of the loop that quickly closed again unless the infrequent conformational switching of the motif stabilized the open state. The functional importance of the PDFG motif is supported by the fact that it is well conserved across PTPs. Bioinformatic analysis shows that the PDFG motif is also conserved, and adopts two distinct conformations, in deiminases, and the related DFG motif is known to function as a conformational switch in many kinases, suggesting that PDFG-like motifs may control transitions between structurally distinct, long-lived conformational states in multiple protein families.