5m4v | pdb_00005m4v
X-ray structure of the mambaquaretin-1, a selective antagonist of the vasopressin type 2 receptor
Structural highlights
FunctionMAMB1_DENAN Selectively interacts with vasopressin V2 receptor (V2R/AVPR2) and fully inhibits three major signaling pathways of this receptor that are GalphaS protein, the interaction with beta-arrestin and activation of MAP kinase (PubMed:28630289, PubMed:35122240). Inhibits vasopressin binding human V2R in the nanomolar range (Ki=5.02 nM), and also potently inhibits vasopressin-induced cAMP production (IC(50)=94 nM) (PubMed:35122240). In vivo, this protein shows an aquaretic effect (PubMed:28630289, PubMed:35122240). Urine output increases and urine osmolality decreases dramatically under treatment with this protein, without differences observed between healthy mice and the pcy mice model of the autosomal-dominant polycystic kidney disease (ADPKD) (PubMed:28630289). This protein does not modify electrolyte, protein and urea excretions in the urine samples, but produces a 3-fold decrease of creatinine levels (PubMed:28630289). Intraperitoneal injection of this protein into the pcy mice significantly reduces the number of renal cysts and the total area of cysts (PubMed:28630289). This protein also shows high efficacy in preventing hyponatremia in rat models (induced by DAVP) (PubMed:33052234). Is highly visible in mice liver and kidney after intravenous injection (PubMed:33052234). Is rapidly eliminated in the liver, whereas it exhibits slow elimination in the kidney due to the high expression of V2R which acts as a reservoir (PubMed:33052234). In addition, its elimination from blood is rapid (PubMed:33052234). Fluorescent MQ1 probes could also be used for imaging V2R-overexpressing cancer cells; note that these probes label the three renal cancer cell lines CAKI-2, ACHN and A498 that highly express V2R (PubMed:33052234). In vivo, does not show any toxicity on animals, even at highest doses tested, such as prostration, spidy coat, appetite or weight loss (PubMed:33052234).[1] [2] [3] Publication Abstract from PubMedPolycystic 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. Green mamba peptide targets type-2 vasopressin receptor against polycystic kidney disease.,Ciolek J, Reinfrank H, Quinton L, Viengchareun S, Stura EA, 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 Proc Natl Acad Sci U S A. 2017 Jul 3;114(27):7154-7159. doi:, 10.1073/pnas.1620454114. Epub 2017 Jun 19. PMID:28630289[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
