6QHC

Crystal Structure of Human Kallikrein 6 in complex with GSK358180B

6QHC の概要

• エントリーDOI: 10.2210/pdb6qhc/pdb
• 分子名称: Kallikrein-6, GLYCEROL, N-(4-CARBAMIMIDOYL-PHENYL)-2-HYDROXY-BENZAMIDE, ... (5 entities in total)
• 機能のキーワード: protease, inhibitor, complex, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 49516.16

構造登録者

Thorpe, J.H. (登録日: 2019-01-16, 公開日: 2019-02-06, 最終更新日: 2024-10-16)

主引用文献

White, G.V.,Edgar, E.V.,Holmes, D.S.,Lewell, X.Q.,Liddle, J.,Polyakova, O.,Smith, K.J.,Thorpe, J.H.,Walker, A.L.,Wang, Y.,Young, R.J.,Hovnanian, A.
Kallikrein 5 inhibitors identified through structure based drug design in search for a treatment for Netherton Syndrome.
Bioorg. Med. Chem. Lett., 29:821-825, 2019

PubMed Abstract: Netherton syndrome (NS) is a rare and debilitating severe autosomal recessive genetic skin disease with high mortality rates particularly in neonates. NS is caused by loss-of-function SPINK5 mutations leading to unregulated kallikrein 5 (KLK5) and kallikrein 7 (KLK7) activity. Furthermore, KLK5 inhibition has been proposed as a potential therapeutic treatment for NS. Identification of potent and selective KLK5 inhibitors would enable further exploration of the disease biology and could ultimately lead to a treatment for NS. This publication describes how fragmentation of known trypsin-like serine protease (TLSP) inhibitors resulted in the identification of a series of phenolic amidine-based KLK5 inhibitors 1. X-ray crystallography was used to find alternatives to the phenol interaction leading to identification of carbonyl analogues such as lactam 13 and benzimidazole 15. These reversible inhibitors, with selectivity over KLK1 (10-100 fold), provided novel starting points for the guided growth towards suitable tool molecules for the exploration of KLK5 biology.

PubMed: 30691925
DOI: 10.1016/j.bmcl.2019.01.020

実験手法

X-RAY DIFFRACTION (1.87 Å)