View source for 6hk4


==Crystal structure of GSK-3B in complex with pyrazine inhibitor C22==
<StructureSection load='6hk4' size='340' side='right'caption='[[6hk4]], [[Resolution|resolution]] 2.50&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6hk4]] is a 3 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=6HK4 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6HK4 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]] 2.5&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=G8E:3-azanyl-6-(4-morpholin-4-ylsulfonylphenyl)-~{N}-pyridin-3-yl-pyrazine-2-carboxamide'>G8E</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MLI:MALONATE+ION'>MLI</scene>, <scene name='pdbligand=PTR:O-PHOSPHOTYROSINE'>PTR</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=6hk4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6hk4 OCA], [https://pdbe.org/6hk4 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6hk4 RCSB], [https://www.ebi.ac.uk/pdbsum/6hk4 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6hk4 ProSAT]</span></td></tr>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
It is widely accepted that drug-target association and dissociation rates directly affect drug efficacy and safety. To rationally optimize drug binding kinetics, one must know the atomic arrangement of the protein-ligand complex during the binding/unbinding process in order to detect stable and metastable states. Whereas experimental approaches can determine kinetic constants with fairly good accuracy, computational approaches based on molecular dynamics (MD) simulations can deliver the atomistic details of the unbinding process. Furthermore, they can also be utilized prospectively to predict residence time (i.e., the inverse of unbinding kinetics constant, koff) with an acceptable level of accuracy. Here, we report a novel method based on adiabatic bias MD with an electrostatics-like collective variable (dubbed elABMD) for sampling protein-ligand dissociation events in two kinases. elABMD correctly ranked a ligand series on glucokinase, in agreement with experimental data and previous calculations. Subsequently, we applied the new method prospectively to a congeneric series of GSK-3beta inhibitors. For this series, new crystal structures were generated and the residence time was experimentally measured with surface plasmon resonance (SPR). There was good agreement between computational predictions and experimental measures, suggesting that elABMD is an innovative and efficient tool for calculating residence times.

Investigating Drug-Target Residence Time in Kinases through Enhanced Sampling Simulations.,Gobbo D, Piretti V, Di Martino RMC, Tripathi SK, Giabbai B, Storici P, Demitri N, Girotto S, Decherchi S, Cavalli A J Chem Theory Comput. 2019 Jul 12. doi: 10.1021/acs.jctc.9b00104. PMID:31246463<ref>PMID:31246463</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6hk4" style="background-color:#fffaf0;"></div>

==See Also==
*[[Glycogen synthase kinase 3 3D structures|Glycogen synthase kinase 3 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Cavalli A]]
[[Category: Decherchi S]]
[[Category: Demitri N]]
[[Category: Di Martino R]]
[[Category: Giabbai B]]
[[Category: Girotto S]]
[[Category: Gobbo D]]
[[Category: Piretti V]]
[[Category: Storici P]]
[[Category: Tripathi SK]]