Aug 2026· Nature Structural & Molecular Biology· Vol 33, pp. 1393 - 1405· 0 citations· 63 references
Medicine
TL;DR
A universal pipeline that integrates an in silico fusion construct screening program, NOAH, with a de novo designed fusion protein to reduce construct optimization effort and enable rapid high-resolution G-protein-coupled receptor structure determination for drug discovery is introduced.
GaMD ensemble docking improved early AM enrichment across all four targets under at least one program, and the Boltz-2 deep-learning program showed minimal sensitivity to GaMD templates and underperformed conventional docking, suggesting its affinity predictions complement rather than replace physics- and empirical-based docking approaches for GPCR AM screening.
T. D. Thompson, Yinglong Miao· bioRxiv· 0 citations
G protein-coupled receptors (GPCRs) are membrane proteins that act as signal transducers across cell membranes. Class B1 GPCRs, a subset of 15 receptors activated by peptide hormones, are involved in important physiological processes and diseases, making them a popular target for drug development. GPCRs are dynamic proteins and can adopt a myriad of conformational states, allowing them to bind and activate multiple intracellular signal transducers, including G proteins and β-arrestins, though all class B1 GPCRs primarily couple to the stimulatory G protein (Gs). Cryogenic electron microscopy (cryo-EM) structures of all class B1 GPCRs bound to Gs are available and provide meaningful insights into receptor function. However, there is a dearth of structural information on class B1 GPCRs in inactive and intermediate states or bound to other signal transducers, meaning we are currently only afforded a small vista into the conformational landscape these GPCRs sample. As cryo-EM-based 3D reconstructions are heavily dependent on protein stability and conformational homogeneity, currently available structures are largely limited to only those most stable conformations (i.e. Gs complexes). The present review focuses on technical aspects of obtaining class B1 GPCR structures using cryo-EM and new in silico methods that allow insight into unseen GPCR conformations, revealing more structural details of the conformational landscape.
Theodore J. Nettleton, P. M. Sexton, D. Wootten et al.· Biochemical Society Transact...· 0 citations
G protein-coupled receptors (GPCRs) mediate a variety of signaling pathways and represent the most common class of pharmaceutical target. While advances in structural biochemistry have provided deep functional insights into key receptors, many of the 800+ human GPCRs remain understudied. We introduce a versatile “deep receptor scanning” platform that can be used to experimentally characterize 766 human GPCRs and 174 known GPCR splice variants in parallel. We use this platform to quantitatively characterize the relative abundance of canonical and alternative receptor transcripts, their translational efficiency, and the plasma membrane expression of each receptor in the context of a recombinant pool of HEK293T cells expressing individual GPCRs. We then employ machine learning to identify specific structural features that are strongly associated with variations in GPCR expression. Our results show that many highly-expressed receptors exhibit systematic differences in hydrophobicity and secondary structure. This experimental platform and informatic approach are compatible with a variety of assays and can be used to efficiently explore the biochemical and pharmacological properties of the GPCRome.
A. Tedman, Muskan Goel, Sohan S. Shah et al.· Nature Communications· 0 citations
This Primer outlines experimental and computational workflows tailored to peptide–GPCR interactions, including in silico peptide mining, deorphanization strategies, library-based screening platforms, modern pathway-resolved biosensor assays, and approaches for peptide stabilization and optimization strategies to address their pharmacokinetic limitations.
J. Hermes, Marin Matic, H. Yeung et al.· Nature Reviews Methods Prime...· 0 citations
This study provides potential lead compounds for the design of small-molecule allosteric drugs targeting class B1 GPCRs and performs conformational sampling and combined dynamic pocket detection algorithms, MDpocket and FTMove, to identify six characteristic cryptic pockets within the dynamic trajectories.
Zhi Dong, Long Cheng, Qingxin Shi et al.· International Journal of Bio...· 0 citations
Results show that current co-folding methods remain unreliable as stand-alone predictors of ion-channel ligand-binding modes and highlight pose sampling, pocket selection, ligand representation and independent structural validation as priorities for methodological development.
Yu Zhu, Taufiq Rahman· Frontiers in Biophysics· 0 citations
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