12cw

D189K thrombin inhibited with D-Phe-Pro-Arg-Chloromethylketone

spinqualitylabelsall models 12cw, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 12cw is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.6Å Ligands: 0G6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease THRB_HUMAN Defects in F2 are the cause of factor II deficiency (FA2D) [MIM:613679. It is a very rare blood coagulation disorder characterized by mucocutaneous bleeding symptoms. The severity of the bleeding manifestations correlates with blood factor II levels. Genetic variations in F2 may be a cause of susceptibility to ischemic stroke (ISCHSTR) [MIM:601367; also known as cerebrovascular accident or cerebral infarction. A stroke is an acute neurologic event leading to death of neural tissue of the brain and resulting in loss of motor, sensory and/or cognitive function. Ischemic strokes, resulting from vascular occlusion, is considered to be a highly complex disease consisting of a group of heterogeneous disorders with multiple genetic and environmental risk factors. Defects in F2 are the cause of thrombophilia due to thrombin defect (THPH1) [MIM:188050. It is a multifactorial disorder of hemostasis characterized by abnormal platelet aggregation in response to various agents and recurrent thrombi formation. Note=A common genetic variation in the 3-prime untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis. Defects in F2 are associated with susceptibility to pregnancy loss, recurrent, type 2 (RPRGL2) [MIM:614390. A common complication of pregnancy, resulting in spontaneous abortion before the fetus has reached viability. The term includes all miscarriages from the time of conception until 24 weeks of gestation. Recurrent pregnancy loss is defined as 3 or more consecutive spontaneous abortions. Function THRB_HUMAN Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C. Functions in blood homeostasis, inflammation and wound healing. Publication Abstract from PubMed BACKGROUND: Thrombin has dual trypsin-like and chymotrypsin-like specificity: it prefers substrates carrying Arg at the site of cleavage (P1) in the activation peptide because of the presence of D189 in the primary specificity (S1) site but can also cleave substrates carrying Phe at P1. OBJECTIVE: Explore the structural basis of the P1-S1 interaction with mutants of D189 and substrates carrying different residues at P1. METHODS: X-ray crystallography is used to solve the structures of thrombin wild-type and mutants D189A, D189F and D189K bound to the irreversible inhibitors H-D-Phe-Pro-Arg-CH(2)Cl (FPRck), H-D-Phe-Pro-Phe-CH(2)Cl (FPFck) and H-D-Phe-Pro-Gln-CH(2)Cl (FPQck). RESULTS: X-ray structures of thrombin wild-type and mutants D189A, D189F and D189K bound to FPRck, FPFck and FPQck are solved at high resolutions, from 1.2 A to 2.5 A. Mutations of D189 do not affect stability of free thrombin but shift the substrate preference from Arg to Phe at P1 and the stability of the inhibited complex from FPRck to FPFck. The structures reveal the flexibility of the S1 site in accommodating side chains of different chemical properties to optimize the P1-S1 interaction. In the D189K-FPRck complex, the inhibitor is trapped in an intermediate state covalently bound only to the catalytic H57 and with the Arg side chain positioned outside of the active site. CONCLUSIONS: The S1 site of thrombin features unexpected structural flexibility and can withstand the replacement of D189 with Ala, Phe or even Lys. The results set the stage for future studies aimed at re-engineering primary specificity in thrombin and other trypsin-like proteases. Structural analysis of the primary specificity of thrombin.,Friet T, Mikhail G, Mohammed BM, Pelc LA, Dei Rossi A, Korolev S, Di Cera E J Thromb Haemost. 2026 Sep 21:S1538-7836(26)00609-4. doi: , 10.1016/j.jtha.2026.09.021. PMID:42767507 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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