5M4V

X-ray structure of the mambaquaretin-1, a selective antagonist of the vasopressin type 2 receptor

5M4V の概要

• エントリーDOI: 10.2210/pdb5m4v/pdb
• 分子名称: Mambaquaretin-1, S-1,2-PROPANEDIOL, CHLORIDE ION, ... (4 entities in total)
• 機能のキーワード: vasopressin antagonist, mamba venom, kunitz, toxin
• 由来する生物種: Dendroaspis angusticeps (eastern green mamba)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 6563.42

構造登録者

Stura, E.A.,Vera, L.,Ciolek, J.,Mourier, G.,Gilles, N. (登録日: 2016-10-19, 公開日: 2017-05-03, 最終更新日: 2024-10-23)

主引用文献

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

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: 28630289
DOI: 10.1073/pnas.1620454114

実験手法

X-RAY DIFFRACTION (1.06 Å)