9DZG

Human GC-A bound to XX16

Summary for 9DZG

• Entry DOI: 10.2210/pdb9dzg/pdb
• Related: 9DZF
• EMDB information: 47329
• Descriptor: Atrial natriuretic peptide receptor 1, XX16 - Heavy Chain, XX16 - Light chain, ... (7 entities in total)
• Functional Keywords: receptor, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 280985.59

Authors

Liu, S.,Huang, X.-Y. (deposition date: 2024-10-16, release date: 2026-01-21, Last modification date: 2026-08-05)

Primary citation

Liu, S.,Manzo, O.,Wang, J.,Zhu, L.,Xiao, F.,Su, Y.C.,Kurre, D.,Liu, W.,Miao, Y.,Di Lorenzo, A.,Huang, X.Y.
Structural insights into single-pass transmembrane receptor GC-A activation by distinct antihypertensive antibodies.
Nat Commun, 17:-, 2026

PubMed 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.

PubMed: 41942428
DOI: 10.1038/s41467-026-71594-7

Experimental method

ELECTRON MICROSCOPY (3.3 Å)