6BFP

Bovine trypsin bound to potent inhibitor

6BFP の概要

• エントリーDOI: 10.2210/pdb6bfp/pdb
• 関連するPDBエントリー: 5TZ9 6ESO
• 分子名称: Cationic trypsin, CALCIUM ION, 3-{2-[(4-carbamimidoylphenyl)carbamoyl]-4-ethenyl-5-methoxyphenyl}-6-[(cyclopropylmethyl)carbamoyl]pyridine-2-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: trypsin protease, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Bos taurus (Bovine)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23877.91

構造登録者

Partridge, J.R.,Choy, R.M. (登録日: 2017-10-26, 公開日: 2018-10-31, 最終更新日: 2024-11-13)

主引用文献

Partridge, J.R.,Choy, R.M.,Silva-Garcia, A.,Yu, C.,Li, Z.,Sham, H.,Metcalf, B.
Structures of full-length plasma kallikrein bound to highly specific inhibitors describe a new mode of targeted inhibition.
J.Struct.Biol., 206:170-182, 2019

PubMed Abstract: Plasma kallikrein (pKal) is a serine protease responsible for cleaving high-molecular-weight kininogen to produce the pro-inflammatory peptide, bradykinin. Unregulated pKal activity can lead to hereditary angioedema (HAE) following excess bradykinin release. HAE attacks can lead to a compromised airway that can be life threatening. As there are limited agents for prophylaxis of HAE attacks, there is a high unmet need for a therapeutic agent for regulating pKal with a high degree of specificity. Here we present crystal structures of both full-length and the protease domain of pKal, bound to two very distinct classes of small-molecule inhibitors: compound 1, and BCX4161. Both inhibitors demonstrate low nM inhibitory potency for pKal and varying specificity for related serine proteases. Compound 1 utilizes a surprising mode of interaction and upon binding results in a rearrangement of the binding pocket. Co-crystal structures of pKal describes why this class of small-molecule inhibitor is potent. Lack of conservation in surrounding residues explains the ∼10,000-fold specificity over structurally similar proteases, as shown by in vitro protease inhibition data. Structural information, combined with biochemical and enzymatic analyses, provides a novel scaffold for the design of targeted oral small molecule inhibitors of pKal for treatment of HAE and other diseases resulting from unregulated plasma kallikrein activity.

PubMed: 30876891
DOI: 10.1016/j.jsb.2019.03.001

実験手法

X-RAY DIFFRACTION (1.292 Å)