6BJR

Crystal structure of prothrombin mutant S101C/A470C

6BJR の概要

• エントリーDOI: 10.2210/pdb6bjr/pdb
• 関連するPDBエントリー: 5EDM
• 分子名称: Prothrombin, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: full-length prothrombin, kringle, closed conformation, hydrolase
• 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: 67060.26

構造登録者

Chinnaraj, M.,Chen, Z.,Pelc, L.,Grese, Z.,Bystranowska, D.,Di Cera, E.,Pozzi, N. (登録日: 2017-11-06, 公開日: 2018-06-27, 最終更新日: 2023-11-15)

主引用文献

Chinnaraj, M.,Chen, Z.,Pelc, L.A.,Grese, Z.,Bystranowska, D.,Di Cera, E.,Pozzi, N.
Structure of prothrombin in the closed form reveals new details on the mechanism of activation.
Sci Rep, 8:2945-2945, 2018

PubMed Abstract: The clotting factor prothrombin exists in equilibrium between closed and open conformations, but the physiological role of these forms remains unclear. As for other allosteric proteins, elucidation of the linkage between molecular transitions and function is facilitated by reagents stabilized in each of the alternative conformations. The open form of prothrombin has been characterized structurally, but little is known about the architecture of the closed form that predominates in solution under physiological conditions. Using X-ray crystallography and single-molecule FRET, we characterize a prothrombin construct locked in the closed conformation through an engineered disulfide bond. The construct: (i) provides structural validation of the intramolecular collapse of kringle-1 onto the protease domain reported recently; (ii) documents the critical role of the linker connecting kringle-1 to kringle-2 in stabilizing the closed form; and (iii) reveals novel mechanisms to shift the equilibrium toward the open conformation. Together with functional studies, our findings define the role of closed and open conformations in the conversion of prothrombin to thrombin and establish a molecular framework for prothrombin activation that rationalizes existing phenotypes associated with prothrombin mutations and points to new strategies for therapeutic intervention.

PubMed: 29440720
DOI: 10.1038/s41598-018-21304-1

実験手法

X-RAY DIFFRACTION (6 Å)