5jfd
From Proteopedia
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==See Also== | ==See Also== | ||
*[[Hirudin 3D structures|Hirudin 3D structures]] | *[[Hirudin 3D structures|Hirudin 3D structures]] | ||
| + | *[[Thrombin 3D Structures|Thrombin 3D Structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
Current revision
Thrombin in complex with (S)-N-(2-(aminomethyl)-5-chlorobenzyl)-1-((benzylsulfonyl)-D-arginyl)pyrrolidine-2-carboxamide
Structural highlights
DiseaseTHRB_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.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] 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.[13] 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.[14] FunctionTHRB_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.[15] Publication Abstract from PubMedStructural fixation of a ligand in its bioactive conformation may, due to entropic reasons, improve affinity. We present a congeneric series of thrombin ligands with a variety of functional groups triggering preorganization prior to binding. Fixation in solution and complex formation have been characterized by crystallography, isothermal titration calorimetry (ITC), and molecular dynamics (MD) simulations. First, we show why these preorganizing modifications do not affect the overall binding mode and how key interactions are preserved. Next, we demonstrate how preorganization thermodynamics can be largely dominated by enthalpy rather than entropy because of the significant population of low-energy conformations. Furthermore, a salt bridge is shielded by actively reducing its surface exposure, thus leading to an enhanced enthalpic binding profile. Our results suggest that the consideration of the ligand solution ensemble by MD simulation is necessary to predict preorganizing modifications that enhance the binding behavior of already promising binders. Strategies for Late-Stage Optimization: Profiling Thermodynamics by Preorganization and Salt Bridge Shielding.,Sandner A, Hufner-Wulsdorf T, Heine A, Steinmetzer T, Klebe G J Med Chem. 2019 Nov 14;62(21):9753-9771. doi: 10.1021/acs.jmedchem.9b01196. Epub, 2019 Nov 4. PMID:31633354[16] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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