5WE8

Crystal structure of WNK1 in complex with N-{(3R)-1-[(4-chlorophenyl)methyl]pyrrolidin-3-yl}-2-(3-methoxyphenyl)-N-methylquinoline-4-carboxamide (compound 8)

5WE8 の概要

• エントリーDOI: 10.2210/pdb5we8/pdb
• 分子名称: Serine/threonine-protein kinase WNK1, MANGANESE (II) ION, PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER, ... (5 entities in total)
• 機能のキーワード: kinase, inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm : Q9H4A3
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 65882.10

構造登録者

Xie, X.,Kohls, D. (登録日: 2017-07-07, 公開日: 2017-08-16, 最終更新日: 2024-03-13)

主引用文献

Yamada, K.,Levell, J.,Yoon, T.,Kohls, D.,Yowe, D.,Rigel, D.F.,Imase, H.,Yuan, J.,Yasoshima, K.,DiPetrillo, K.,Monovich, L.,Xu, L.,Zhu, M.,Kato, M.,Jain, M.,Idamakanti, N.,Taslimi, P.,Kawanami, T.,Argikar, U.A.,Kunjathoor, V.,Xie, X.,Yagi, Y.I.,Iwaki, Y.,Robinson, Z.,Park, H.M.
Optimization of Allosteric With-No-Lysine (WNK) Kinase Inhibitors and Efficacy in Rodent Hypertension Models.
J. Med. Chem., 60:7099-7107, 2017

PubMed Abstract: The observed structure-activity relationship of three distinct ATP noncompetitive With-No-Lysine (WNK) kinase inhibitor series, together with a crystal structure of a previously disclosed allosteric inhibitor bound to WNK1, led to an overlay hypothesis defining core and side-chain relationships across the different series. This in turn enabled an efficient optimization through scaffold morphing, resulting in compounds with a good balance of selectivity, cellular potency, and pharmacokinetic profile, which were suitable for in vivo proof-of-concept studies. When dosed orally, the optimized compound reduced blood pressure in mice overexpressing human WNK1, and induced diuresis, natriuresis and kaliuresis in spontaneously hypertensive rats (SHR), confirming that this mechanism of inhibition of WNK kinase activity is effective at regulating cardiovascular homeostasis.

PubMed: 28771350
DOI: 10.1021/acs.jmedchem.7b00708

実験手法

X-RAY DIFFRACTION (2.006 Å)