5M4V
X-ray structure of the mambaquaretin-1, a selective antagonist of the vasopressin type 2 receptor
Summary for 5M4V
| Entry DOI | 10.2210/pdb5m4v/pdb |
| Descriptor | Mambaquaretin-1, S-1,2-PROPANEDIOL, CHLORIDE ION, ... (4 entities in total) |
| Functional Keywords | vasopressin antagonist, mamba venom, kunitz, toxin |
| Biological source | Dendroaspis angusticeps (eastern green mamba) |
| Total number of polymer chains | 1 |
| Total formula weight | 6563.42 |
| Authors | Stura, E.A.,Vera, L.,Ciolek, J.,Mourier, G.,Gilles, N. (deposition date: 2016-10-19, release date: 2017-05-03, Last modification date: 2024-10-23) |
| Primary citation | Ciolek, J.,Reinfrank, H.,Quinton, L.,Viengchareun, S.,Stura, E.A.,Vera, L.,Sigismeau, S.,Mouillac, B.,Orcel, H.,Peigneur, S.,Tytgat, J.,Droctove, L.,Beau, F.,Nevoux, J.,Lombes, M.,Mourier, G.,De Pauw, E.,Servent, D.,Mendre, C.,Witzgall, R.,Gilles, N. Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease. Proc. Natl. Acad. Sci. U.S.A., 114:7154-7159, 2017 Cited by PubMed Abstract: Polycystic kidney diseases (PKDs) are genetic disorders that can cause renal failure and death in children and adults. Lowering cAMP in cystic tissues through the inhibition of the type-2 vasopressin receptor (V2R) constitutes a validated strategy to reduce disease progression. We identified a peptide from green mamba venom that exhibits nanomolar affinity for the V2R without any activity on 155 other G-protein-coupled receptors or on 15 ionic channels. Mambaquaretin-1 is a full antagonist of the V2R activation pathways studied: cAMP production, beta-arrestin interaction, and MAP kinase activity. This peptide adopts the Kunitz fold known to mostly act on potassium channels and serine proteases. Mambaquaretin-1 interacts selectively with the V2R through its first loop, in the same manner that aprotinin inhibits trypsin. Injected in mice, mambaquaretin-1 increases in a dose-dependent manner urine outflow with concomitant reduction of urine osmolality, indicating a purely aquaretic effect associated with the in vivo blockade of V2R. CD1-pcy/pcy mice, a juvenile model of PKD, daily treated with 13 [Formula: see text]g of mambaquaretin-1 for 99 d, developed less abundant (by 33%) and smaller (by 47%) cysts than control mice. Neither tachyphylaxis nor apparent toxicity has been noted. Mambaquaretin-1 represents a promising therapeutic agent against PKDs. PubMed: 28630289DOI: 10.1073/pnas.1620454114 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.06 Å) |
Structure validation
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