7JWX

Crystal Structure of Trypsin Bound O-methyl Benzamidine

7JWX の概要

• エントリーDOI: 10.2210/pdb7jwx/pdb
• 分子名称: Cationic trypsin, 4-[(1-{(1S,2S)-1-[1-(4-aminobutyl)-1H-1,2,3-triazol-4-yl]-2-methylbutyl}-1H-1,2,3-triazol-4-yl)methoxy]-3-methoxybenzene-1-carboximidamide, CALCIUM ION, ... (7 entities in total)
• 機能のキーワード: hydrolase inhibitor, 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: 4
• 化学式量合計: 95826.94

構造登録者

Packianathan, C.,Laganowsky, A. (登録日: 2020-08-26, 公開日: 2021-08-04, 最終更新日: 2024-10-30)

主引用文献

Lyu, R.L.,Joy, S.,Packianathan, C.,Laganowsky, A.,Burgess, K.
Small molecule peptidomimetic trypsin inhibitors: validation of an EKO binding mode, but with a twist.
Org.Biomol.Chem., 20:2075-2080, 2022

PubMed Abstract: Examination of a series of naturally-occurring trypsin inhibitor proteins, led to identification of a set of three residues (which we call the "interface triplet") to be determinant of trypsin binding affinity, hence excellent templates for small molecule mimicry. Consequently, we attempted to use the Exploring Key Orientation (EKO) strategy developed in our lab to evaluate small molecules that mimic the interface triplet regions of natural trypsin inhibitors, and hence potentially might bind and inhibit the catalytic activity of trypsin. A bis-triazole scaffold ("TT-mer") was the most promising of the molecules evaluated . Twelve such compounds were synthesized and assayed against trypsin, among which the best showed a of 2.1 μM. X-ray crystallography revealed a high degree of matching between an illustrative TT-mer's actual binding mode and that of the mimics that overlaid the interface triplet in the crystal structure. Deviation of the third side chain from the PPI structure seems to be due to alleviation of an unfavorable dipole-dipole interaction in the small molecule's actual bound conformation.

PubMed: 35225309
DOI: 10.1039/d1ob02127c

実験手法

X-RAY DIFFRACTION (2.38 Å)