Modeling the Orthosteric Binding Site of the G Protein-Coupled Odorant Receptor OR5K1.

With approximately 400 encoding genes in humans, odorant receptors (ORs) are the largest subfamily of class A G protein-coupled receptors (GPCRs). Despite its high relevance and representation, the odorant-GPCRome is structurally poorly characterized: no experimental structures are available, and the low sequence identity of ORs to experimentally solved GPCRs is a significant challenge for their modeling. Moreover, the receptive range of most ORs is unknown. The odorant receptor OR5K1 was recently and comprehensively characterized in terms of cognate agonists. Here, we report two additional agonists and functional data of the most potent compound on two mutants, L1043.32 and L2556.51. Experimental data was used to guide the investigation of the binding modes of OR5K1 ligands into the orthosteric binding site using structural information from AI-driven modeling, as recently released in the AlphaFold Protein Structure Database, and from homology modeling. Induced-fit docking simulations were used to sample the binding site conformational space for ensemble docking. Mutagenesis data guided side chain residue sampling and model selection. We obtained models that could better rationalize the different activity of active (agonist) versus inactive molecules with respect to starting models and also capture differences in activity related to minor structural differences. Therefore, we provide a model refinement protocol that can be applied to model the orthosteric binding site of ORs as well as that of GPCRs with low sequence identity to available templates.

Combined Effect of Obesity and Mobility Limitation with Incidence of Type 2 Diabetes and Mortality in Chinese Elderly.

This article aims to examine the effect of mobility limitation and obesity on the risk of new incidence of type 2 diabetes mellitus (T2DM) and mortality. The design was a cohort study (n = 1075) among adults aged 60 years and older. Obesity was defined as body-mass index greater than or equal to 28 kg/m2. Mobility limitation was defined as participants scoring in the top 20% on the timed up and go test or in the slowest 20% for the 4-m walking test. The mean age of the study population was 67.4 ± 5.4 years (age range: 60-86 years), and 57.4% were women. Overall, 5.1% of women and 1.9% of men had both obesity and mobility limitations. During 3-year follow-up, the new incidence of T2DM was 2.98% and the adjusted risk of the new incidence of T2DM was progressively greater in obese subjects without mobility limitation, but not greater in the single mobility limitation subjects. The combination of mobility limitation and obesity (odds ratio = 10.3, 95% confidence interval = 2.25-70.13) has a significantly higher risk than obesity only or mobility limitation only. What is more, obesity with mobility limitation could be an independent predictor of 3-year mortality compared with the other subjects. We demonstrated the associations between obesity and mobility limitation and thus the increased risk of developing, with the combination over time, T2DM and mortality.