4KEL

Atomic resolution crystal structure of Kallikrein-Related Peptidase 4 complexed with a modified SFTI inhibitor FCQR(N)

4KEL の概要

• エントリーDOI: 10.2210/pdb4kel/pdb
• 関連するPDBエントリー: 2bdg 2bdh 2bdi 4K1E 4K8Y 4KGA
• 関連するBIRD辞書のPRD_ID: PRD_001059
• 分子名称: Kallikrein-4, Trypsin inhibitor 1 (3 entities in total)
• 機能のキーワード: bowman-birk inhibitor, protease, protease inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 25505.87

構造登録者

Ilyichova, O.V.,Swedberg, J.E.,de Veer, S.J.,Sit, K.C.,Harris, J.M.,Buckle, A.M. (登録日: 2013-04-25, 公開日: 2014-04-30, 最終更新日: 2024-11-20)

主引用文献

Riley, B.T.,Ilyichova, O.,de Veer, S.J.,Swedberg, J.E.,Wilson, E.,Hoke, D.E.,Harris, J.M.,Buckle, A.M.
KLK4 Inhibition by Cyclic and Acyclic Peptides: Structural and Dynamical Insights into Standard-Mechanism Protease Inhibitors.
Biochemistry, 58:2524-2533, 2019

PubMed Abstract: Sunflower trypsin inhibitor (SFTI-1) is a 14 amino acid serine protease inhibitor. The dual antiparallel β-sheet arrangement of SFTI-1 is stabilized by an N-terminal-C-terminal backbone cyclization and a further disulfide bridge to form a final bicyclic structure. This constrained structure is further rigidified by an extensive network of internal hydrogen bonds. Thus, the structure of SFTI-1 in solution resembles the protease-bound structure, reducing the entropic penalty upon protease binding. When cleaved at the scissile bond, it is thought that the rigidifying features of SFTI-1 maintain its structure, allowing the scissile bond to be reformed. The lack of structural plasticity for SFTI-1 is proposed to favor initial protease binding and continued occupancy in the protease active site, resulting in an equilibrium between the cleaved and uncleaved inhibitor in the presence of a protease. We have determined, at 1.15 Å resolution, the X-ray crystal structures of complexes between human kallikrein-related peptidase 4 (KLK4) and SFTI-FCQR(Asn14) and between KLK4 and an acyclic form of the same inhibitor, SFTI-FCQR(Asn14)[1,14], with the latter displaying a cleaved scissile bond. Structural analysis and MD simulations together reveal the roles of the altered contact sequence, intramolecular hydrogen bonding network, and backbone cyclization in altering the state of SFTI's scissile bond ligation at the protease active site. Taken together, the data presented reveal insights into the role of dynamics in the standard-mechanism inhibition and suggest that modifications on the non-contact strand may be a useful, underexplored approach for generating further potent or selective SFTI-based inhibitors against members of the serine protease family.

PubMed: 31058493
DOI: 10.1021/acs.biochem.9b00191

実験手法

X-RAY DIFFRACTION (1.148 Å)