8TGA

Complex of NPR1 ectodomain and REGN5381 Fab in an active-like state with no ANP bound

Summary for 8TGA

• Entry DOI: 10.2210/pdb8tga/pdb
• EMDB information: 41234
• Descriptor: Atrial natriuretic peptide receptor 1, REGN5381 Fab light chain, REGN5381 Fab heavy chain (3 entities in total)
• Functional Keywords: atrial natriuretic peptide, antibody, activator, pulmonary hypertension, immune system
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 6
• Total formula weight: 200812.78

Authors

Franklin, M.C.,Romero Hernandez, A. (deposition date: 2023-07-12, release date: 2024-07-17, Last modification date: 2024-10-30)

Primary citation

Dunn, M.E.,Kithcart, A.,Kim, J.H.,Ho, A.J.,Franklin, M.C.,Romero Hernandez, A.,de Hoon, J.,Botermans, W.,Meyer, J.,Jin, X.,Zhang, D.,Torello, J.,Jasewicz, D.,Kamat, V.,Garnova, E.,Liu, N.,Rosconi, M.,Pan, H.,Karnik, S.,Burczynski, M.E.,Zheng, W.,Rafique, A.,Nielsen, J.B.,De, T.,Verweij, N.,Pandit, A.,Locke, A.,Chalasani, N.,Melander, O.,Schwantes-An, T.H.,Baras, A.,Lotta, L.A.,Musser, B.J.,Mastaitis, J.,Devalaraja-Narashimha, K.B.,Rankin, A.J.,Huang, T.,Herman, G.,Olson, W.,Murphy, A.J.,Yancopoulos, G.D.,Olenchock, B.A.,Morton, L.
Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone.
Nature, 633:654-661, 2024

PubMed Abstract: Heart failure is a leading cause of morbidity and mortality. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure.

PubMed: 39261724
DOI: 10.1038/s41586-024-07903-1

Experimental method

ELECTRON MICROSCOPY (3.65 Å)