4bao: Difference between revisions
New page: '''Unreleased structure''' The entry 4bao is ON HOLD Authors: Xue, Y., Musil, D. Description: Thrombin in complex with inhibitor |
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The | ==Thrombin in complex with inhibitor== | ||
<StructureSection load='4bao' size='340' side='right'caption='[[4bao]], [[Resolution|resolution]] 1.87Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4bao]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Hirudo_medicinalis Hirudo medicinalis] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BAO OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BAO FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.87Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MVF:(2S)-1-[(2R)-2-[(2-AZANYL-2-OXIDANYLIDENE-ETHYL)AMINO]-2-CYCLOHEXYL-ETHANOYL]-N-[(4-CARBAMIMIDOYLPHENYL)METHYL]AZETIDINE-2-CARBOXAMIDE'>MVF</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=TYS:O-SULFO-L-TYROSINE'>TYS</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4bao FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bao OCA], [https://pdbe.org/4bao PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bao RCSB], [https://www.ebi.ac.uk/pdbsum/4bao PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bao ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/HIRV2_HIRME HIRV2_HIRME] Hirudin is a potent thrombin-specific protease inhibitor. It forms a stable non-covalent complex with alpha-thrombin, thereby abolishing its ability to cleave fibrinogen. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
For improved understanding of drug-target interactions, the effect of introducing substituted amine residues with increased chain length in the P3 residue of the thrombin inhibitor melagatran was explored. Inhibition, kinetic and thermodynamic data obtained via stopped-flow spectroscopy (SF), isothermal microcalorimetry (ITC) and surface plasmon resonance (SPR) biosensor analysis were interpreted with the help of X-ray crystal structures of the enzyme inhibitor complexes. The association rate became faster when increasing the lipophilicity of the inhibitors. This was coupled to an increased enthalpic component and a corresponding decreased entropic component. The dissociation rates were reduced upon increasing the chain length, with only a smaller increase and decrease of the enthalpic and entropic components, respectively. Overall, the affinity increased with increasing chain length, with similar changes in the enthalpic and entropic components. ITC analysis confirmed the equilibrium data from SPR analysis, showing that melagatran was the most enthalpy driven interaction. Structural analysis of the thrombin-inhibitor complex showed that the orientation of the P1 and P2 parts of the molecules was very similar, but that there were significant differences in the interaction between the terminal part of the P3 side chain and the binding pocket. A combination of charge repulsion, H-bonds and hydrophobic interactions could be used to explain the observed kinetic and thermodynamic profiles for the ligands. In conclusion, changes in the structure of a lead compound can have significant effects on its interaction with the target that translate directly into kinetic and thermodynamic effects. In contrast to what may be intuitively expected, hydrogen bond formation and breakage is not necessarily reflected in enthalpy gains and losses, respectively. | |||
Identification of Structure-Kinetic and Structure-Thermodynamic Relationships for Thrombin Inhibitors.,Winquist J, Geschwindner S, Xue Y, Gustavsson L, Musil D, Deinum J, Danielson UH Biochemistry. 2013 Jan 4. PMID:23290007<ref>PMID:23290007</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 4bao" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Hirudin 3D structures|Hirudin 3D structures]] | |||
*[[Thrombin 3D Structures|Thrombin 3D Structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Hirudo medicinalis]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Musil D]] | |||
[[Category: Xue Y]] | |||
Latest revision as of 05:43, 21 November 2024
Thrombin in complex with inhibitorThrombin in complex with inhibitor
Structural highlights
FunctionHIRV2_HIRME Hirudin is a potent thrombin-specific protease inhibitor. It forms a stable non-covalent complex with alpha-thrombin, thereby abolishing its ability to cleave fibrinogen. Publication Abstract from PubMedFor improved understanding of drug-target interactions, the effect of introducing substituted amine residues with increased chain length in the P3 residue of the thrombin inhibitor melagatran was explored. Inhibition, kinetic and thermodynamic data obtained via stopped-flow spectroscopy (SF), isothermal microcalorimetry (ITC) and surface plasmon resonance (SPR) biosensor analysis were interpreted with the help of X-ray crystal structures of the enzyme inhibitor complexes. The association rate became faster when increasing the lipophilicity of the inhibitors. This was coupled to an increased enthalpic component and a corresponding decreased entropic component. The dissociation rates were reduced upon increasing the chain length, with only a smaller increase and decrease of the enthalpic and entropic components, respectively. Overall, the affinity increased with increasing chain length, with similar changes in the enthalpic and entropic components. ITC analysis confirmed the equilibrium data from SPR analysis, showing that melagatran was the most enthalpy driven interaction. Structural analysis of the thrombin-inhibitor complex showed that the orientation of the P1 and P2 parts of the molecules was very similar, but that there were significant differences in the interaction between the terminal part of the P3 side chain and the binding pocket. A combination of charge repulsion, H-bonds and hydrophobic interactions could be used to explain the observed kinetic and thermodynamic profiles for the ligands. In conclusion, changes in the structure of a lead compound can have significant effects on its interaction with the target that translate directly into kinetic and thermodynamic effects. In contrast to what may be intuitively expected, hydrogen bond formation and breakage is not necessarily reflected in enthalpy gains and losses, respectively. Identification of Structure-Kinetic and Structure-Thermodynamic Relationships for Thrombin Inhibitors.,Winquist J, Geschwindner S, Xue Y, Gustavsson L, Musil D, Deinum J, Danielson UH Biochemistry. 2013 Jan 4. PMID:23290007[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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