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.
Data availability
The source data underlying Fig. 6c–e, Supplementary Fig. 2c, f, and Supplementary Table 1 are provided as a Source Data file. The cryo-EM density maps and corresponding coordinates have been deposited to the EMDB and PDB, respectively, under the following accession codes: EMD-47328 and PDB 9DZF (GC-A–XX16–ANP); EMD-47329 and PDB 9DZG (GC-A–XX16); EMD-47330 and PDB 9DZH (GC-A–REGN5308–ANP); EMD-47331 and PDB 9DZJ (GC-A–2X REGN5308–ANP); EMD-47332 and PDB 9DZK (GC-A–REGN5308). The input structure and parameter files and output trajectories of GaMD simulations for the ANP-bound GC-A, ANP-XX16-bound, ANP-REGN5308-bound, and ANP-2X REGN5308-bound GC-A systems are available on the Figshare webserver: https://doi.org/10.6084/m9.figshare.29508473. The input structure and parameter files and output trajectories of LiGaMD3 simulations for the ANP-bound, ANP-XX16-bound, and ANP-REGN5308-bound GC-A systems are available on the Figshare webserver: https://doi.org/10.6084/m9.figshare.29508899. Publicly available PDB entries used in this study are available under the accession codes 9BCQ, 8TGA, and 8TG9. Source data are provided with this paper.
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Acknowledgements
We thank members of our research groups and Dr. Larry Palmer for helpful discussion and comments on the manuscript, the Laboratory for BioMolecular Structure (LBMS) staff, and the New York Structural Biology Center staff for the help with the cryo-EM data acquisition. This work was supported by NIH grant HL177433 (X.Y.H.) and the startup funding project 27110 at the University of North Carolina-Chapel Hill (Y.M.). Supercomputing resources were used with allocation award TG-MCB180049 through the Advanced Cyberinfrastructure Coordination Ecosystem: Services & Support (ACCESS) program and project M2874 through the National Energy Research Scientific Computing Center (Y.M.). LBMS is supported by the DOE Office of Biological and Environmental Research (KP1607011). Some of this work was performed at the Simons Electron Microscopy Center and National Resource for Automated Molecular Microscopy located at the New York Structural Biology Center, supported by grants from the Simons Foundation (SF349247), NYSTAR, the Agouron Institute (F00316), and the NIH (GM103310, OD019994).
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S.L. expressed and purified GC-A and the antibodies, made cryo-EM grids, performed cryo-EM screening, data collection, structure determination, model building, and figure preparation. O.M. performed the animal experiments under the supervision of A.D.L. J.W. and F.X. performed MD simulations under the supervision of Y.M. L.Z. performed cGMP assays under the supervision of W.L. Y.C.S. and D.K. performed functional assays for the mutant GC-As. X.Y.H. supervised the project, interpreted data, and wrote the manuscript. All authors contributed towards the final version of the manuscript.
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Liu, S., Manzo, O., Wang, J. et al. Structural insights into single-pass transmembrane receptor GC-A activation by distinct antihypertensive antibodies. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71594-7
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DOI: https://doi.org/10.1038/s41467-026-71594-7
