5TP0

Human mesotrypsin in complex with diminazene

5TP0 の概要

• エントリーDOI: 10.2210/pdb5tp0/pdb
• 分子名称: Trypsin-3, CALCIUM ION, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: trypsin, serine-type endopeptidase, serine hydrolase, complex with small molecule drug, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24979.10

構造登録者

Kayode, O.,Soares, A.,Radisky, E.S. (登録日: 2016-10-19, 公開日: 2017-05-17, 最終更新日: 2023-10-04)

主引用文献

Kayode, O.,Huang, Z.,Soares, A.S.,Caulfield, T.R.,Dong, Z.,Bode, A.M.,Radisky, E.S.
Small molecule inhibitors of mesotrypsin from a structure-based docking screen.
PLoS ONE, 12:e0176694-e0176694, 2017

PubMed Abstract: PRSS3/mesotrypsin is an atypical isoform of trypsin, the upregulation of which has been implicated in promoting tumor progression. To date there are no mesotrypsin-selective pharmacological inhibitors which could serve as tools for deciphering the pathological role of this enzyme, and could potentially form the basis for novel therapeutic strategies targeting mesotrypsin. A virtual screen of the Natural Product Database (NPD) and Food and Drug Administration (FDA) approved Drug Database was conducted by high-throughput molecular docking utilizing crystal structures of mesotrypsin. Twelve high-scoring compounds were selected for testing based on lowest free energy docking scores, interaction with key mesotrypsin active site residues, and commercial availability. Diminazene (CID22956468), along with two similar compounds presenting the bis-benzamidine substructure, was validated as a competitive inhibitor of mesotrypsin and other human trypsin isoforms. Diminazene is the most potent small molecule inhibitor of mesotrypsin reported to date with an inhibitory constant (Ki) of 3.6±0.3 μM. Diminazene was subsequently co-crystalized with mesotrypsin and the crystal structure was solved and refined to 1.25 Å resolution. This high resolution crystal structure can now offer a foundation for structure-guided efforts to develop novel and potentially more selective mesotrypsin inhibitors based on similar molecular substructures.

PubMed: 28463992
DOI: 10.1371/journal.pone.0176694

実験手法

X-RAY DIFFRACTION (1.25 Å)