6zn0: Difference between revisions

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<StructureSection load='6zn0' size='340' side='right'caption='[[6zn0]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
<StructureSection load='6zn0' size='340' side='right'caption='[[6zn0]], [[Resolution|resolution]] 1.59&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6zn0]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Cricetulus_griseus Cricetulus griseus]. 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>
<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]] 1.59&#8491;</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]] 1.59&#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=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='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>
<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>
</table>
== Function ==
[https://www.uniprot.org/uniprot/KAPCA_CRIGR KAPCA_CRIGR] Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Negatively regulates tight junctions (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT) (By similarity). Phosphorylates APOBEC3G and AICDA (By similarity).
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Cricetulus griseus]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Heine A]]
[[Category: Heine A]]
[[Category: Klebe G]]
[[Category: Klebe G]]
[[Category: Oebbeke M]]
[[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

Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.59Å
Ligands:, , , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Oebbeke M, Siefker C, Wagner B, Heine A, Klebe G. Fragment Binding to Kinase Hinge: If Charge Distribution and Local pKa Shifts Mislead Popular Bioisosterism Concepts. Angew Chem Int Ed Engl. 2020 Oct 6. doi: 10.1002/anie.202011295. PMID:33021032 doi:http://dx.doi.org/10.1002/anie.202011295

6zn0, resolution 1.59Å

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