View source for 4yhk


==Reversal Agent for Dabigatran==
<StructureSection load='4yhk' size='340' side='right'caption='[[4yhk]], [[Resolution|resolution]] 2.21&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4yhk]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4YHK OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4YHK 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]] 2.21&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><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>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=4yhk FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4yhk OCA], [https://pdbe.org/4yhk PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4yhk RCSB], [https://www.ebi.ac.uk/pdbsum/4yhk PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4yhk ProSAT]</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.

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>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4yhk" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Nar H]]
[[Category: Schiele F]]