9DZJ
Human GC-A bound to ANP and 2xREGN5308
Summary for 9DZJ
| Entry DOI | 10.2210/pdb9dzj/pdb |
| Related | 9DZF 9DZG 9DZH |
| EMDB information | 47331 |
| Descriptor | REGN5308 - Heavy chain, REGN5308 - Light chain, Atrial natriuretic peptide receptor 1, ... (9 entities in total) |
| Functional Keywords | receptor, membrane protein |
| Biological source | Mus musculus More |
| Total number of polymer chains | 7 |
| Total formula weight | 333786.09 |
| 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 Cited by 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: 41942428DOI: 10.1038/s41467-026-71594-7 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.7 Å) |
Structure validation
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