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TitleEntropy drives the ligand recognition in G-protein-coupled receptor subtypes.
Journal, issue, pagesProc Natl Acad Sci U S A, Vol. 121, Issue 30, Page e2401091121, Year 2024
Publish dateJul 23, 2024
AuthorsXin Yang / Pei Zhou / Siyuan Shen / Qian Hu / Chenyu Tian / Anjie Xia / Yifei Wang / Zhiqian Yang / Jinshan Nan / Yangli Zhou / Shasha Chen / Xiaowen Tian / Chao Wu / Guifeng Lin / Liting Zhang / Kexin Wang / Tao Zheng / Jun Zou / Wei Yan / Zhenhua Shao / Shengyong Yang /
PubMed AbstractAchieving ligand subtype selectivity within highly homologous subtypes of G-protein-coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism ...Achieving ligand subtype selectivity within highly homologous subtypes of G-protein-coupled receptor (GPCR) is critical yet challenging for GPCR drug discovery, primarily due to the unclear mechanism underlying ligand subtype selectivity, which hampers the rational design of subtype-selective ligands. Herein, we disclose an unusual molecular mechanism of entropy-driven ligand recognition in cannabinoid (CB) receptor subtypes, revealed through atomic-level molecular dynamics simulations, cryoelectron microscopy structure, and mutagenesis experiments. This mechanism is attributed to the distinct conformational dynamics of the receptor's orthosteric pocket, leading to variations in ligand binding entropy and consequently, differential binding affinities, which culminate in specific ligand recognition. We experimentally validated this mechanism and leveraged it to design ligands with enhanced or ablated subtype selectivity. One such ligand demonstrated favorable pharmacokinetic properties and significant efficacy in rodent inflammatory analgesic models. More importantly, it is precisely due to the high subtype selectivity obtained based on this mechanism that this ligand does not show addictive properties in animal models. Our findings elucidate the unconventional role of entropy in CB receptor subtype selectivity and suggest a strategy for rational design of ligands to achieve entropy-driven subtype selectivity for many pharmaceutically important GPCRs.
External linksProc Natl Acad Sci U S A / PubMed:39024109 / PubMed Central
MethodsEM (single particle)
Resolution3.13 Å
Structure data

38039

8x3l

EMDB-38039, PDB-8x3l:
Cryo-EM structure of CB2-G protein complex
Method: EM (single particle) / Resolution: 3.13 Å

Chemicals


ChemComp, No image

ChemComp-XWD:
Unknown entry

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / CB2 / Gi1 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-IMMUNE SYSTEM complex

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