1k21
HUMAN THROMBIN-INHIBITOR COMPLEX
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OverviewOverview
The binding of a series of low molecular weight ligands towards trypsin, and thrombin has been studied by isothermal titration calorimetry and, protein crystallography. In a series of congeneric ligands, surprising, changes of protonation states occur and are overlaid on the binding, process. They result from induced pK(a) shifts depending on the local, environment experienced by the ligand and protein functional groups in the, complex (induced dielectric fit). They involve additional heat effects, that must be corrected before any conclusion on the binding enthalpy, (DeltaH) and entropy (DeltaS) can be drawn. After correction, trends in, both contributions can be interpreted in structural terms with respect to, the hydrogen bond inventory or residual ligand motions. For all inhibitors, studied, a strong negative heat capacity change (DeltaC(p)) is detected, thus binding becomes more exothermic and entropically less favourable with, increasing temperature. Due to a mutual compensation, Gibbs free energy, remains virtually unchanged. The strong negative DeltaC(p) value cannot, solely be explained by the removal of hydrophobic surface portions of the, protein or ligand from water exposure. Additional contributions must be, considered, presumably arising from modulations of the local water, structure, changes in vibrational modes or other ordering parameters. For, thrombin, smaller negative DeltaC(p) values are observed for ligand, binding in the presence of sodium ions compared to the other alkali ions, probably due to stabilising effects on the protein or changes in the bound, water structure.
DiseaseDisease
Known diseases associated with this structure: Dysprothrombinemia OMIM:[176930], Hyperprothrombinemia OMIM:[176930], Hypoprothrombinemia OMIM:[176930]
About this StructureAbout this Structure
1K21 is a Protein complex structure of sequences from Hirudo medicinalis and Homo sapiens with NA and IGN as ligands. Active as Thrombin, with EC number 3.4.21.5 Full crystallographic information is available from OCA.
ReferenceReference
Factorising ligand affinity: a combined thermodynamic and crystallographic study of trypsin and thrombin inhibition., Dullweber F, Stubbs MT, Musil D, Sturzebecher J, Klebe G, J Mol Biol. 2001 Oct 26;313(3):593-614. PMID:11676542
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