1THR

STRUCTURES OF THROMBIN COMPLEXES WITH A DESIGNED AND A NATURAL EXOSITE INHIBITOR

1THR の概要

• エントリーDOI: 10.2210/pdb1thr/pdb
• 分子名称: ALPHA-THROMBIN (SMALL SUBUNIT), ALPHA-THROMBIN (LARGE SUBUNIT), HIRULLIN, ... (4 entities in total)
• 機能のキーワード: hydrolase(serine proteinase)
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Secreted, extracellular space: P00734 P00734; Secreted: P26631
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 35450.32

構造登録者

Qiu, X.,Yin, M.,Padmanabhan, K.P.,Krstenansky, J.L.,Tulinsky, A. (登録日: 1993-06-16, 公開日: 1994-01-31, 最終更新日: 2024-11-20)

主引用文献

Qiu, X.,Yin, M.,Padmanabhan, K.P.,Krstenansky, J.L.,Tulinsky, A.
Structures of thrombin complexes with a designed and a natural exosite peptide inhibitor.
J.Biol.Chem., 268:20318-20326, 1993

PubMed Abstract: The structures of two hirudin-based fibrinogen recognition exosite peptide inhibitors with significantly different sequences complexed with alpha-thrombin at a site distinct from the active site (exosite) have been determined crystallographically at 2.2 and 2.3 A resolution. One is a designed synthetic peptide with some nonconventional amino acid residues (MDL-28050), and the other is a natural COOH-terminal peptide isolated from the leech Hirudinaria manillensis (hirullin P18). The structures have been refined by restrained least squares methods to R values of 0.161 and 0.155, respectively. The first stretch of each peptide, corresponding to hirudin 55-59, associates with thrombin similar to hirudin and hirugen (hirudin 53-64). Although the remaining residues of the inhibitors interact with and bind to thrombin, the binding is accomplished. through a rigid body conformational adjustment of the peptide with respect to the conformation displayed by hirudin and hirugen (40 degrees rotation about the Ile59, CA-C bond). This causes the side groups of cyclohexylalanine 64' of MDL-28050 and Ile60, of hirullin to point in the opposite direction of the all important Tyr63, ring of hirudin and hirugen but permits the residues to penetrate and interact with the 3(10) turn hydrophobic binding pocket of thrombin. Thus, the hydrophobic interaction is accomplished in a different way by virtue of the substrate conformational readjustment. The results show that the first stretch of peptide makes concerted and efficient binding interactions with thrombin, and the peptide positions of the inhibitors are fairly specific and homologous so that the stretch appears to be related to specific recognition associated with the exosite. The relative flexibility of structure and sequence of the second stretch is a display of tolerance of imprecision by thrombin in its COOH-terminal hydrophobic association with hirudin-based inhibitors.

PubMed: 8376390

実験手法

X-RAY DIFFRACTION (2.3 Å)