6BTP

BMP1 complexed with a hydroxamate

6BTP の概要

• エントリーDOI: 10.2210/pdb6btp/pdb
• 分子名称: Bone morphogenetic protein 1, THIOCYANATE ION, ZINC ION, ... (5 entities in total)
• 機能のキーワード: endopeptidase, 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: 46712.11

構造登録者

Gampe, R.,Shewchuk, L. (登録日: 2017-12-07, 公開日: 2018-08-08, 最終更新日: 2024-11-20)

主引用文献

Kallander, L.S.,Washburn, D.,Hilfiker, M.A.,Eidam, H.S.,Lawhorn, B.G.,Prendergast, J.,Fox, R.,Dowdell, S.,Manns, S.,Hoang, T.,Zhao, S.,Ye, G.,Hammond, M.,Holt, D.A.,Roethke, T.,Hong, X.,Reid, R.A.,Gampe, R.,Zhang, H.,Diaz, E.,Rendina, A.R.,Quinn, A.M.,Willette, B.
Reverse Hydroxamate Inhibitors of Bone Morphogenetic Protein 1.
ACS Med Chem Lett, 9:736-740, 2018

PubMed Abstract: Bone Morphogenetic Protein 1 (BMP1) inhibition is a potential method for treating fibrosis because BMP1, a member of the zinc metalloprotease family, is required to convert pro-collagen to collagen. A novel class of reverse hydroxamate BMP1 inhibitors was discovered, and cocrystal structures with BMP1 were obtained. The observed binding mode is unique in that the small molecule occupies the nonprime side of the metalloprotease pocket providing an opportunity to build in metalloprotease selectivity. Structure-guided modification of the initial hit led to the identification of an oral tool compound with selectivity over other metalloproteases. Due to irreversible inhibition of cytochrome P450 3A4 for this chemical class, the risk of potential drug-drug interactions was managed by optimizing the series for subcutaneous injection.

PubMed: 30034610
DOI: 10.1021/acsmedchemlett.8b00173

実験手法

X-RAY DIFFRACTION (1.93 Å)