4z84: Difference between revisions
New page: '''Unreleased structure''' The entry 4z84 is ON HOLD until Paper Publication Authors: Lund, B.A., Alam, K.A., Engh, R.A. Description: PKAB3 in complex with pyrrolidine inhibitor 34a [[... |
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==PKAB3 in complex with pyrrolidine inhibitor 34a== | |||
<StructureSection load='4z84' size='340' side='right'caption='[[4z84]], [[Resolution|resolution]] 1.55Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4z84]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bos_taurus Bos taurus] and [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Z84 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Z84 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]] 1.554Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MOH:METHANOL'>MOH</scene>, <scene name='pdbligand=NVX:7-[(3S,4R)-4-(3-CHLOROPHENYL)CARBONYLPYRROLIDIN-3-YL]-3H-QUINAZOLIN-4-ONE'>NVX</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=4z84 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4z84 OCA], [https://pdbe.org/4z84 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4z84 RCSB], [https://www.ebi.ac.uk/pdbsum/4z84 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4z84 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/IPKA_HUMAN IPKA_HUMAN] Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Protein kinases continue to be hot targets in drug discovery research, as they are involved in many essential cellular processes and their deregulation can lead to a variety of diseases. A series of 32 enantiomerically pure inhibitors was synthesized and tested towards protein kinase A (PKA) and protein kinase B mimic PKAB3 (PKA triple mutant). The ligands bind to the hinge region, ribose pocket, and glycine-rich loop at the ATP site. Biological assays showed high potency against PKA, with Ki values in the low nanomolar range. The investigation demonstrates the significance of targeting the often neglected glycine-rich loop for gaining high binding potency. X-ray co-crystal structures revealed a multi-facetted network of ligand-loop interactions for the tightest binders, involving orthogonal dipolar contacts, sulfur and other dispersive contacts, amide-pi stacking, and H-bonding to organofluorine, besides efficient water replacement. The network was analyzed in a computational approach. | |||
Addressing the Glycine-Rich Loop of Protein Kinases by a Multi-Facetted Interaction Network: Inhibition of PKA and a PKB Mimic.,Lauber BS, Hardegger LA, Asraful AK, Lund BA, Dumele O, Harder M, Kuhn B, Engh RA, Diederich F Chemistry. 2015 Nov 18. doi: 10.1002/chem.201503552. PMID:26578105<ref>PMID:26578105</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 4z84" style="background-color:#fffaf0;"></div> | ||
[[Category: Alam | |||
[[Category: Engh | ==See Also== | ||
*[[CAMP-dependent protein kinase 3D structures|CAMP-dependent protein kinase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bos taurus]] | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Alam KA]] | |||
[[Category: Engh RA]] | |||
[[Category: Lund BA]] | |||
Latest revision as of 11:39, 23 October 2024
PKAB3 in complex with pyrrolidine inhibitor 34aPKAB3 in complex with pyrrolidine inhibitor 34a
Structural highlights
FunctionIPKA_HUMAN Extremely potent competitive inhibitor of cAMP-dependent protein kinase activity, this protein interacts with the catalytic subunit of the enzyme after the cAMP-induced dissociation of its regulatory chains. Publication Abstract from PubMedProtein kinases continue to be hot targets in drug discovery research, as they are involved in many essential cellular processes and their deregulation can lead to a variety of diseases. A series of 32 enantiomerically pure inhibitors was synthesized and tested towards protein kinase A (PKA) and protein kinase B mimic PKAB3 (PKA triple mutant). The ligands bind to the hinge region, ribose pocket, and glycine-rich loop at the ATP site. Biological assays showed high potency against PKA, with Ki values in the low nanomolar range. The investigation demonstrates the significance of targeting the often neglected glycine-rich loop for gaining high binding potency. X-ray co-crystal structures revealed a multi-facetted network of ligand-loop interactions for the tightest binders, involving orthogonal dipolar contacts, sulfur and other dispersive contacts, amide-pi stacking, and H-bonding to organofluorine, besides efficient water replacement. The network was analyzed in a computational approach. Addressing the Glycine-Rich Loop of Protein Kinases by a Multi-Facetted Interaction Network: Inhibition of PKA and a PKB Mimic.,Lauber BS, Hardegger LA, Asraful AK, Lund BA, Dumele O, Harder M, Kuhn B, Engh RA, Diederich F Chemistry. 2015 Nov 18. doi: 10.1002/chem.201503552. PMID:26578105[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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