4yho: Difference between revisions

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'''Unreleased structure'''
==Reversal Agent for Dabigatran==
<StructureSection load='4yho' size='340' side='right' caption='[[4yho]], [[Resolution|resolution]] 1.82&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4yho]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YHO OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4YHO FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4CC:N-[(2-{[(4-CARBAMIMIDOYLPHENYL)AMINO]METHYL}-1-METHYL-1H-BENZIMIDAZOL-5-YL)CARBONYL]-N-PYRIDIN-2-YL-BETA-ALANINE'>4CC</scene></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=4yho FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yho OCA], [http://pdbe.org/4yho PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4yho RCSB], [http://www.ebi.ac.uk/pdbsum/4yho PDBsum]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Novel oral anticoagulants are effective and safe alternatives to vitamin-K antagonists for anticoagulation therapy. However, anticoagulation therapy in general is associated with an elevated risk of bleeding. Idarucizumab is a reversal agent for the direct thrombin inhibitor, dabigatran etexilate (Pradaxa(R)) and is currently in Phase 3 studies. Here, we report data on the antibody fragment aDabi-Fab2, a putative backup molecule for idarucizumab. Although aDabi-Fab2 completely reversed effects of dabigatran in a rat model in vivo, we observed significantly reduced duration of action compared to idarucizumab. Rational protein engineering, based on the X-ray structure of aDabi-Fab2, led to the identification of mutant Y103W. The mutant had optimized shape complementarity to dabigatran while maintaining an energetically favored hydrogen bond. It displayed increased affinity for dabigatran, mainly driven by a slower off-rate. Interestingly, the increased residence time translated into longer duration of action in vivo. It was thus possible to further enhance the efficacy of aDabi-Fab2 based on rational design, giving it the potential to serve as a back-up candidate for idarucizumab.


The entry 4yho is ON HOLD  until Paper Publication
Structure-guided residence time optimization of a dabigatran reversal agent.,Schiele F, van Ryn J, Litzenburger T, Ritter M, Seeliger D, Nar H MAbs. 2015 Jun 5:0. PMID:26047352<ref>PMID:26047352</ref>


Authors: Schiele, F., Nar, H.
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 
</div>
Description: Reversal Agent for Dabigatran
<div class="pdbe-citations 4yho" style="background-color:#fffaf0;"></div>
[[Category: Unreleased Structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Nar, H]]
[[Category: Nar, H]]
[[Category: Schiele, F]]
[[Category: Schiele, F]]
[[Category: Antibody]]
[[Category: Antidote]]
[[Category: Dabigatran]]
[[Category: Immune system]]
[[Category: Pradaxa]]
[[Category: Reversal agent]]
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