3evj: Difference between revisions
No edit summary |
No edit summary |
||
| Line 1: | Line 1: | ||
==Intermediate structure of antithrombin bound to the natural pentasaccharide== | ==Intermediate structure of antithrombin bound to the natural pentasaccharide== | ||
<StructureSection load='3evj' size='340' side='right' caption='[[3evj]], [[Resolution|resolution]] 3.00Å' scene=''> | <StructureSection load='3evj' size='340' side='right' caption='[[3evj]], [[Resolution|resolution]] 3.00Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3evj]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EVJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3EVJ FirstGlance]. <br> | <table><tr><td colspan='2'>[[3evj]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3EVJ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3EVJ FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand= | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=NTO:TRISULFOAMINO+HEPARIN+PENTASACCHARIDE'>NTO</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1nq9|1nq9]], [[2b5t|2b5t]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1nq9|1nq9]], [[2b5t|2b5t]]</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3evj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3evj OCA], [http://pdbe.org/3evj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3evj RCSB], [http://www.ebi.ac.uk/pdbsum/3evj PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3evj FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3evj OCA], [http://pdbe.org/3evj PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3evj RCSB], [http://www.ebi.ac.uk/pdbsum/3evj PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3evj ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
| Line 21: | Line 22: | ||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3evj ConSurf]. | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3evj ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Antithrombin (AT) is the most important inhibitor of coagulation proteases. Its activity is stimulated by glycosaminoglycans, such as heparin, through allosteric and template mechanisms. AT utilises an induced-fit mechanism to bind with high affinity to a pentasaccharide sequence found in about one-third of heparin chains. The conformational changes behind this mechanism have been characterised by several crystal structures of AT in the absence and in the presence of pentasaccharide. Pentasaccharide binding ultimately results in a conformational change that improves affinity by about 1000-fold. Crystal structures show several differences, including the expulsion of the hinge region of the reactive centre loop from beta-sheet A, which is known to be critical for the allosteric activation of AT. Here, we present data that reveal an energetically distinct intermediate on the path to full activation where the majority of conformational changes have already occurred. A crystal structure of this intermediate shows that the hinge region is in a native-like state in spite of having the pentasaccharide bound in the normal fashion. We engineered a disulfide bond to lock the hinge in its native position to determine the energetic contributions of the initial and final conformational events. Approximately 60% of the free-energy contribution of conformational change is provided by the final step of hinge-region expulsion and subsequent closure of the main beta-sheet A. A new analysis of the individual structural changes provides a plausible mechanism for propagation of conformational change from the heparin binding site to the remote hinge region in beta-sheet A. | |||
The critical role of hinge-region expulsion in the induced-fit heparin binding mechanism of antithrombin.,Langdown J, Belzar KJ, Savory WJ, Baglin TP, Huntington JA J Mol Biol. 2009 Mar 13;386(5):1278-89. PMID:19452598<ref>PMID:19452598</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 3evj" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||