9VWT

The catalytic domain of human plasma kallikrein with peptide inhibitor 070

9VWT の概要

• エントリーDOI: 10.2210/pdb9vwt/pdb
• 分子名称: Plasma kallikrein light chain, peptide inhibitor (3 entities in total)
• 機能のキーワード: s1 pocket, serine protease, hereditary angioedema, peptide inhibitor, peptide binding protein
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 27941.82

構造登録者

Xu, M. (登録日: 2025-07-17, 公開日: 2025-08-06, 最終更新日: 2025-08-13)

主引用文献

Lin, H.,Xu, M.,Jiang, L.,Yuan, C.,Jiang, C.,Huang, M.,Li, J.,Xu, P.
Water-medicated specifically targeting the S1 pockets among serine proteases using an arginine analogue.
Bioorg.Chem., 152:107734-107734, 2024

PubMed Abstract: Because of the high similarity in structure and sequence, it is challenging to distinguish the S1 pocket among serine proteases, primarily due to the only variability at residue 190 (A190 and S190). Peptide or protein-based inhibitors typically target the negatively charged S1 pocket using lysine or arginine as the P1 residue, yet neither discriminates between the two S1 pocket variants. This study introduces two arginine analogues, L-4-guanidinophenylalanine (12) and L-3-(N-amidino-4-piperidyl)alanine (16), as novel P1 residues in peptide inhibitors. 16 notably enhances affinities across all tested proteases, whereas 12 specifically improved affinities towards proteases possessing S190 in the S1 pocket. By crystallography and molecular dynamics simulations, we discovered a novel mechanism involving a water exchange channel at the bottom of the S1 pocket, modulated by the variation of residue 190. Additionally, the specificity of 12 towards the S190-presenting S1 pocket is dependent on this water channel. This study not only introduces novel P1 residues to engineer inhibitory potency and specificity of peptide inhibitors targeting serine proteases, but also unveils a water-mediated molecular mechanism of targeting serine proteases.

PubMed: 39167871
DOI: 10.1016/j.bioorg.2024.107734

実験手法

X-RAY DIFFRACTION (1.77 Å)