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==Crystal structure of the cAMP-dependent protein kinase A in complex with phenol==
==Crystal structure of the cAMP-dependent protein kinase A in complex with phenol==
<StructureSection load='6z44' size='340' side='right'caption='[[6z44]]' scene=''>
<StructureSection load='6z44' size='340' side='right'caption='[[6z44]], [[Resolution|resolution]] 1.38&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Z44 OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6Z44 FirstGlance]. <br>
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6Z44 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6Z44 FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6z44 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z44 OCA], [http://pdbe.org/6z44 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6z44 RCSB], [http://www.ebi.ac.uk/pdbsum/6z44 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6z44 ProSAT]</span></td></tr>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.38&#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=IPH:PHENOL'>IPH</scene>, <scene name='pdbligand=MRD:(4R)-2-METHYLPENTANE-2,4-DIOL'>MRD</scene>, <scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</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=6z44 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6z44 OCA], [https://pdbe.org/6z44 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6z44 RCSB], [https://www.ebi.ac.uk/pdbsum/6z44 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6z44 ProSAT]</span></td></tr>
</table>
</table>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Medicinal-chemistry optimization follows strategies replacing functional groups and attaching larger substituents at a promising lead scaffold. Well-established bioisosterism rules are considered, however, it is difficult to estimate whether the introduced modifications really match the required properties at a binding site. The electron density distribution and pKa values are modulated influencing protonation states and bioavailability. Considering the adjacent H-bond donor/acceptor pattern of the hinge binding motif in a kinase, we studied by crystallography a set of fragments to map the required interaction pattern. Unexpectedly, benzoic acid and benzamidine, decorated with the correct substituents, are totally bioisosteric just as carboxamide and phenolic OH. A mono-dentate pyridine nitrogen out-performs bi-dentate functionalities. The importance of correctly designing pKa values of attached functional groups by additional substituents at the parent scaffold is rendered prominent.
Fragment Binding to Kinase Hinge: If Charge Distribution and Local pKa Shifts Mislead Popular Bioisosterism Concepts.,Oebbeke M, Siefker C, Wagner B, Heine A, Klebe G Angew Chem Int Ed Engl. 2020 Oct 6. doi: 10.1002/anie.202011295. PMID:33021032<ref>PMID:33021032</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6z44" style="background-color:#fffaf0;"></div>
==See Also==
*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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