9JH3

CMF-019 with APLNR-Gi complex

This is a non-PDB format compatible entry.

Summary for 9JH3

• Entry DOI: 10.2210/pdb9jh3/pdb
• EMDB information: 61470
• Descriptor: Guanine nucleotide-binding protein G(i) subunit alpha-1, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1, Apelin receptor, ... (6 entities in total)
• Functional Keywords: complex, agonist, membrane protein, membrane protein-immune system complex, membrane protein/immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 5
• Total formula weight: 154169.07

Authors

Tian, X.W.,Zhao, C.,Feng, Y.Y.,Shao, Z.H. (deposition date: 2024-09-08, release date: 2025-04-23, Last modification date: 2025-05-14)

Primary citation

Sun, Q.,Tian, X.,Tan, L.,Deng, Y.,Liu, S.,Xiong, Y.,Feng, Y.,Wang, Y.,Zhang, L.,Zhu, J.,Xiao, H.,Shao, Z.,Guo, Y.,Yan, W.,Li, T.,Ouyang, L.
Multiscale biased chemical space remodeling for developing APLNR agonists with anti-HFpEF efficacy.
Proc.Natl.Acad.Sci.USA, 122:e2423432122-e2423432122, 2025

PubMed Abstract: Heart failure with preserved ejection fraction (HFpEF) represents a significant global health burden, yet effective pharmacotherapies remain elusive. The angiotensin-like 1 receptor, also known as the apelin receptor (APLNR), is a promising target for treating HFpEF due to its role in modulating cardiovascular function. Despite the cardioprotective effects of endogenous ligand, apelin, achieving G-protein-biased agonism for therapeutic benefit poses a significant challenge. In this study, we unravel the biased signal transduction pathway mediated by a reported partial G-protein-biased APLNR agonist CMF-019 and developed a biased chemical space remodeling approach to identify exclusive G-protein-biased agonists targeting APLNR. These agonists exhibited enhanced Gi-protein-biased function and protective effects in both in vitro and in vivo. Our findings not only enhance comprehension of APLNR-biased agonism but also establish drug design strategies for modifying and reshaping biased chemical landscapes in other G-protein-coupled receptors (GPCRs).

PubMed: 40314976
DOI: 10.1073/pnas.2423432122

Experimental method

ELECTRON MICROSCOPY (2.93 Å)