Structural insights into single-pass transmembrane receptor GC-A activation by distinct antihypertensive antibodies. Nat Commun 2026 Apr 06;17(1)
Date
04/07/2026Pubmed ID
41942428Pubmed Central ID
PMC13230927DOI
10.1038/s41467-026-71594-7Scopus ID
2-s2.0-105040739152 (requires institutional sign-in at Scopus site)Abstract
The single-pass transmembrane receptor guanylyl cyclase A (GC-A), also known as natriuretic peptide receptor A (NPR-A) or NPR1, regulates blood pressure through vasodilation and natriuresis, making it a promising therapeutic target for hypertension and heart failure. We describe two monoclonal antibodies, XX16 and REGN5308, that differentially activate GC-A. Using cryo-electron microscopy and molecular dynamics simulations, we reveal that XX16 stabilizes GC-A in an active conformation even without its ligand ANP, whereas REGN5308 requires ANP to fully promote receptor activation. Both antibodies increase ANP binding affinity to GC-A and enhance GC-A-mediated cGMP signaling, although XX16 exerts a stronger stabilizing influence on ATP and GTP binding. In a mouse model of obesity-induced hypertension, XX16 treatment significantly reduces blood pressure, underscoring its therapeutic potential. These findings outline the structural and functional basis of GC-A activation by antibody positive allosteric modulators, offering strategies for durable antihypertensive therapies and improved management of cardiovascular diseases.
Author List
Liu S, Manzo O, Wang J, Zhu L, Xiao F, Su YC, Kurre D, Liu W, Miao Y, Di Lorenzo A, Huang XYAuthor
Wei Liu PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsAntibodies, Monoclonal
Antihypertensive Agents
Atrial Natriuretic Factor
Blood Pressure
Cryoelectron Microscopy
Cyclic GMP
HEK293 Cells
Humans
Hypertension
Mice
Molecular Dynamics Simulation
Receptors, Atrial Natriuretic Factor
Signal Transduction
