6zn0: Difference between revisions
New page: '''Unreleased structure''' The entry 6zn0 is ON HOLD until Paper Publication Authors: Description: Category: Unreleased Structures |
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==Crystal structure of cAMP-dependent protein kinase A (CHO PKA) in complex with isonicotinamidine== | |||
<StructureSection load='6zn0' size='340' side='right'caption='[[6zn0]], [[Resolution|resolution]] 1.59Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6ZN0 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6ZN0 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]] 1.59Å</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=MRD:(4R)-2-METHYLPENTANE-2,4-DIOL'>MRD</scene>, <scene name='pdbligand=NTN:ISONICOTINAMIDINE'>NTN</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=6zn0 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zn0 OCA], [https://pdbe.org/6zn0 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6zn0 RCSB], [https://www.ebi.ac.uk/pdbsum/6zn0 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6zn0 ProSAT]</span></td></tr> | |||
</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®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6zn0" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Heine A]] | |||
[[Category: Klebe G]] | |||
[[Category: Oebbeke M]] | |||
Latest revision as of 13:48, 23 October 2024
Crystal structure of cAMP-dependent protein kinase A (CHO PKA) in complex with isonicotinamidineCrystal structure of cAMP-dependent protein kinase A (CHO PKA) in complex with isonicotinamidine
Structural highlights
Publication Abstract from PubMedMedicinal-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[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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