Structural Basis for Ligand Recognition and Functional Selectivity at Angiotensin Receptor*♦

By Haitao Zhang, Hamiyet Unal, R. Desnoyer, G. Han, N. Patel, Vsevolod Katritch, S. Karnik, Vadim Cherezov, Raymond C. Stevens. 2015

163 citations recorded by the source corpus.

Background: Angiotensin receptor (AT1R) blockers are critical therapeutics used to treat cardiovascular disease. Results: We solved the AT1R-olmesartan structure and identified specific interactions for olmesartan derivatives with different functions. Conclusion: Our results identified residues critical for the binding of different ligands and allosteric modulation by sodium ion. Significance: Our results provide new insights into the structural basis for ligand recognition and functional selectivity at AT1R. Angiotensin II type 1 receptor (AT1R) is the primary blood pressure regulator. AT1R blockers (ARBs) have been widely used in clinical settings as anti-hypertensive drugs and share a similar chemical scaffold, although even minor variations can lead to distinct therapeutic efficacies toward cardiovascular etiologies. The structural basis for AT1R modulation by different peptide and non-peptide ligands has remained elusive. Here, we report the crystal structure of the human AT1R in complex with an inverse agonist olmesartan (BenicarTM), a highly potent anti-hypertensive drug. Olmesartan is anchored to the receptor primarily by the residues Tyr-351.39, Trp-842.60, and Arg-167ECL2, similar to the antagonist ZD7155, corroborating a common binding mode of different ARBs. Using docking simulations and site-directed mutagenesis, we identified specific interactions between AT1R and different ARBs, including olmesartan derivatives with inverse agonist, neutral antagonist, or agonist activities. We further observed that the mutation N1113.35A in the putative sodium-binding site affects binding of the endogenous peptide agonist angiotensin II but not the β-arrestin-biased peptide TRV120027.

Subfields: Computational Theory and Mathematics, Molecular Biology, Pharmacology

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Jens Meiler

Citations in the corpus

Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs (2020, background): “Three receptors (4ZUD [43], 3PBL [44], and 2RH1 [5]) were identified that had at least 5 templates in each identity range (30–39%, 25–29%, 20–24%, and 15–19%).”
A Structural Framework for GPCR Chemogenomics: What's In a Residue Number? (2018, methodology): “6, PDB: 4YAY [77], 4ZUD [76]), however, F was predicted to contact the ligand but later it was found to be located deeper in the TM bundle facing the membrane, and other important interactions with Y and R were missed by the method.”