Predicted structure and cell signaling of TAS2R14 reveal receptor hyper-flexibility for detecting diverse bitter tastes.

The 25 human bitter taste receptors (TAS2Rs) are expressed on taste and extra-oral cells representing an integrated chemosensory system. The archetypal TAS2R14 is activated by > 150 topographically diverse agonists, raising the question of how this uncharacteristic accommodation is achieved for these GPCRs. We report the computationally derived structure of TAS2R14 with binding sites and energies for five highly diverse agonists. Remarkably, the binding pocket is the same for all five agonists. The energies derived from molecular dynamics are consistent with experiments determining signal transduction coefficients in live cells. TAS2R14 accommodates agonists through the breaking of a TMD3 H-bond instead of the prototypic strong salt bridge, a TMD1,2,7 interaction different from Class A GPCRs, and agonist-promoted TMD3 salt bridges for high affinity (which we confirmed by receptor mutagenesis). Thus, the broadly tuned TAS2Rs accommodate diverse agonists via a single (vs multiple) binding pocket through unique TM interactions for sensing disparate micro-environments.

Relationships between surrogate measures of mechanical and psychophysiological load, patellar tendon adaptations, and neuromuscular performance in NCAA division I men's volleyball athletes.

Introduction: Patellar tendon adaptations occur in response to mechanical load. Appropriate loading is necessary to elicit positive adaptations with increased risk of injury and decreased performance likely if loading exceeds the capacity of the tendon. The aim of the current study was to examine intra-individual associations between workloads and patellar tendon properties and neuromuscular performance in collegiate volleyball athletes. Methods: National Collegiate Athletics Association Division I men's volleyball athletes (n = 16, age: 20.33 ± 1.15 years, height: 193.50 ± 6.50 cm, body mass: 84.32 ± 7.99 kg, bodyfat%: 13.18 ± 4.72%) competing across 9 weeks of in-season competition participated. Daily measurements of external workloads (i.e., jump count) and internal workloads [i.e., session rating of perceived exertion (sRPE)] were recorded. Weekly measurements included neuromuscular performance assessments (i.e., countermovement jump, drop jump), and ultrasound images of the patellar tendon to evaluate structural adaptations. Repeated measures correlations (r-rm) assessed intra-individual associations among performance and patellar tendon metrics. Results: Workload measures exhibited significant negative small to moderate (r-rm =-0.26-0.31) associations with neuromuscular performance, negative (r-rm = -0.21-0.30), and positive (r-rm = 0.20-0.32) small to moderate associations with patellar tendon properties. Discussion: Monitoring change in tendon composition and performance adaptations alongside workloads may inform evidence-based frameworks toward managing and reducing the risk of the development of patellar tendinopathy in collegiate men's volleyball athletes.

Revisiting the Assessment of Strength, Power, and Change of Direction in Collegiate American Football Athletes.

ABSTRACT: Burke, AA, Guthrie, BM, Magee, M, Miller, AD, and Jones, MT. Revisiting the assessment of strength, power, and change of direction in collegiate american football athletes. J Strength Cond Res 37(8): 1623-1627, 2023-The primary purpose was to assess the effect of strength on vertical jump (VJ) and change of direction (COD) with a secondary purpose to examine if these relationships were moderated by the sport position group through path analysis using structural equation modeling. Subjects were collegiate American football athletes grouped by skill (SK; n = 98) and nonskill (NS; n = 83) sport position groups. Maximal strength was assessed by 1 repetition maximum back squat and hang clean (HC). Vertical jump was used to evaluate power. Change of direction was assessed through the 20-yard shuttle (i.e., 5-10-5) test. Multigroup path analysis examined causal pathways among variables and moderating effects of sport position. The final model revealed that VJ fully mediated the relationship between HC and COD (HC-VJ: ß = 0.408, p < 0.001; VJ-COD: ß = -0.376, p < 0.001; and HC-COD: ß = -0.137, p = 0.17) in SK. The NS showed only direct effects of HC on COD ( ß = -0.335, p < 0.001). These findings suggest that strength does not solely explain COD ability but also can serve to enhance underpinning qualities, such as relative force production in the VJ. Relationships between strength, power, and COD are different depending on the positional group. The results provide further insight into performance outcomes in field tests. It is recommended that sport position differences be considered when assessing and analyzing physical qualities in a team setting within the sport of American football.

Synergic Effects in the Activation of the Sweet Receptor GPCR Heterodimer for Various Sweeteners Predicted Using Molecular Metadynamics Simulations.

The sweet taste is elicited by activation of the TAS1R2/1R3 heterodimer G protein-coupled receptor. This is a therapeutic target for treatment of obesity and metabolic dysfunctions. Sweetener blends provide attractive strategies to lower the sugar level while preserving the attractive taste of food. To understand the synergic effect of various sweetener blend combinations of artificial and natural sweeteners, we carried out our molecular dynamics studies using predicted structures of the TAS1R2/1R3 heterodimer and predicted structures for the sweeteners. We used as a measure of activation the intracellular ionic lock distance between transmembrane helices 3 and 6 of TAS1R3. We find that full synergic combinations [rebaudioside A (Reb-A)/acesulfame K and Reb-A/sucralose] and partial synergic combinations (sucralose/acesulfame K) show significantly more negative changes in the free energy compared to single-ligand cases, while a pair known to be suppressive (saccharin and acesulfame K) shows significantly less changes than for the single-ligand case. This study provides an atomistic understanding of the mechanism for synergy and identifies new combinations of sweeteners to reduce the caloric content for treating diseases.

Physical Performance Assessments of Strength and Power in Women Collegiate Athletes.

Limited research exists on physical performance assessments for women collegiate athletes. The current cross-sectional study compared field-based tests of muscular strength and power and investigated their relationship. Sports included field hockey, volleyball, soccer, and softball. Tests of one repetition maximum (1-RM) back squat, 1-RM bench press, vertical jump, and standing long jump were administered. A one-way analysis of variance (ANOVA) assessed differences across sports. Bivariate Pearson correlation coefficients examined relationships among tests. It was hypothesized sports with a higher anaerobic nature (volleyball, softball) would outperform those with higher aerobic nature (field hockey, soccer). Softball had the highest 1-RM bench press and 1-RM back squat (p < 0.001) compared to field hockey, volleyball, and soccer. Further, softball had the highest vertical jump (p < 0.001) compared to field hockey and soccer, but did not differ from volleyball. There were no differences across sports for standing long jump. Correlations (p < 0.001) existed between 1-RM back squat and 1-RM bench press (n = 663, r = 0.56), and vertical jump and standing long jump (n = 160, r = 0.64). Results demonstrate strength and power differences among collegiate women's sports. Softball consistently outperformed others in bench press, back squat, and vertical jump, which may be due to the demand of power embedded in the nature of the sport. These data provide descriptive measures of physical performance assessments and may assist practitioners with goal setting and program design.

Predicted Structure of Fully Activated Tas1R3/1R3' Homodimer Bound to G Protein and Natural Sugars: Structural Insights into G Protein Activation by a Class C Sweet Taste Homodimer with Natural Sugars.

The Tas1R3 G protein-coupled receptor constitutes the main component of sweet taste sensory response in humans via forming a heterodimer with Tas1R2 or a homodimer with Tas1R3. The Tas1R3/1R3' homodimer serves as a low-affinity sweet taste receptor, stimulating gustducin G protein (GGust) signaling in the presence of a high concentration of natural sugars. This provides an additional means to detect the taste of natural sugars, thereby differentiating the flavors between natural sugars and artificial sweeteners. We report here the predicted 3D structure of active state Tas1R3/1R3' homodimer complexed with heterotrimeric GGust and sucrose. We discovered that the GGust makes ionic anchors to intracellular loops 1 and 2 of Tas1R3 while the Gα-α5 helix engages the cytoplasmic region extensively through salt bridge and hydrophobic interactions. We show that in the activation of this complex the Venus flytrap domains of the homodimer undergo a remarkable twist up to ∼100° rotation around the vertical axis to adopt a closed-closed conformation while the intracellular region relaxes to an open-open conformation. We find that binding of sucrose to the homodimer stabilizes a preactivated conformation with a largely open intracellular region that recruits and activates the GGust. Upon activation, the Gα subunit spontaneously opens up the nucleotide-binding site, making nucleotide exchange facile for signaling. This activation of GGust promotes the interdomain twist of the Venus flytrap domains. These structures and transformations could potentially be a basis for the design of new sweeteners with higher activity and less unpleasant flavors.

Predicted structure of fully activated human bitter taste receptor TAS2R4 complexed with G protein and agonists.

Bitter taste is sensed by bitter taste receptors (TAS2Rs) that belong to the G protein-coupled receptor (GPCR) superfamily. In addition to bitter taste perception, TAS2Rs have been reported recently to be expressed in many extraoral tissues and are now known to be involved in health and disease. Despite important roles of TAS2Rs in biological functions and diseases, no crystal structure is available to help understand the signal transduction mechanism or to help develop selective ligands as new therapeutic targets. We report here the three-dimensional structure of the fully activated TAS2R4 human bitter taste receptor predicted using the GEnSeMBLE complete sampling method. This TAS2R4 structure is coupled to the gustducin G protein and to each of several agonists. We find that the G protein couples to TAS2R4 by forming strong salt bridges to each of the three intracellular loops, orienting the activated Gα5 helix of the Gα subunit to interact extensively with the cytoplasmic region of the activated receptor. We find that the TAS2Rs exhibit unique motifs distinct from typical Class A GPCRs, leading to a distinct activation mechanism and a less stable inactive state. This fully activated bitter taste receptor complex structure provides insight into the signal transduction mechanism and into ligand binding to TAS2Rs.

Patient Satisfaction With a New, High Accuracy Blood Glucose Meter That Provides Personalized Guidance, Insight, and Encouragement.

BACKGROUND: Accurate self-monitoring of blood glucose (SMBG) is a key component of effective self-management of glycemic control. METHODS: The OneTouch Verio Reflect and OneTouch Ultra Plus Reflect BG monitoring systems were evaluated for accuracy in a clinical setting. Subjects also used the meters for a one-week trial period and reported their level of satisfaction with meter features. RESULTS: Both systems were accurate over a wide glucose range and met lay user and system accuracy BG standards described in ISO15197:2015. Subjects felt that the features of a meter with a dynamic color range indicator and personalized guidance, insight, and encouragement could provide significant benefits to them in the management of their diabetes. CONCLUSIONS: Both meter systems were accurate over a wide glucose range and the features of the meter and messages were well received by patients in a short take-home trial. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT0351542.

Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists.

The sweet taste in humans is mediated by the TAS1R2/TAS1R3 G protein-coupled receptor (GPCR), which belongs to the class C family that also includes the metabotropic glutamate and γ-aminobutyric acid receptors. We report here the predicted 3D structure of the full-length TAS1R2/TAS1R3 heterodimer, including the Venus Flytrap Domains (VFDs) [in the closed-open (co) active conformation], the cysteine-rich domains (CRDs), and the transmembrane domains (TMDs) at the TM56/TM56 interface. We observe that binding of agonists to VFD2 of TAS1R2 leads to major conformational changes to form a TM6/TM6 interface between TMDs of TAS1R2 and TAS1R3, which is consistent with the activation process observed biophysically on the metabotropic glutamate receptor 2 homodimer. We find that the initial effect of the agonist is to pull the bottom part of VFD3/TAS1R3 toward the bottom part of VFD2/TAS1R2 by ∼6 Šand that these changes get transmitted from VFD2 of TAS1R2 (where agonists bind) through the VFD3 and the CRD3 to the TMD3 of TAS1R3 (which couples to the G protein). These structural transformations provide a detailed atomistic mechanism for the activation process in GPCR, providing insights and structural details that can now be validated through mutation experiments.