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4c38

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Revision as of 21:16, 4 August 2016

PKA-S6K1 Chimera with compound 21e (CCT239066) bound

Structural highlights

4c38 is a 2 chain structure with sequence from Bovin. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
NonStd Res:	,
Related:	4c33, 4c34, 4c35, 4c36, 4c37
Activity:	cAMP-dependent protein kinase, with EC number 2.7.11.11
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[KAPCA_BOVIN] 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, TRPC1 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+). TRPC1 activation by phosphorylation promotes Ca(2+) influx, essential for the increase in permeability induced by thrombin in confluent endothelial monolayers. PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Regulates negatively tight junction (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. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. 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).

Publication Abstract from PubMed

The ribosomal P70 S6 kinases play a crucial role in PI3K/mTOR regulated signalling pathways and are therefore potential targets for the treatment of a variety of diseases including diabetes and cancer. In this study we describe the identification of three series of chemically distinct S6K1 inhibitors. In addition, we report a novel PKA-S6K1 chimeric protein with five mutations in or near its ATP-binding site, which was used to determine the binding mode of two of the three inhibitor series, and provided a robust system to aid the optimisation of the oxadiazole-substituted benzimidazole inhibitor series. We show that the resulting oxadiazole-substituted aza-benzimidazole is a potent and ligand efficient S6 kinase inhibitor, which blocks the phosphorylation of RPS6 at Ser235/236 in TSC negative HCV29 human bladder cancer cells by inhibiting S6 kinase activity and thus provides a useful tool compound to investigate the function of S6 kinases.

The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design.,Couty S, Westwood IM, Kalusa A, Cano C, Travers J, Boxall K, Chow CL, Burns S, Schmitt J, Pickard L, Barillari C, McAndrew PC, Clarke PA, Linardopoulos S, Griffin RJ, Aherne GW, Raynaud FI, Workman P, Jones K, van Montfort RL Oncotarget. 2013 Aug 25. PMID:24072592^[1]

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

References

↑ Couty S, Westwood IM, Kalusa A, Cano C, Travers J, Boxall K, Chow CL, Burns S, Schmitt J, Pickard L, Barillari C, McAndrew PC, Clarke PA, Linardopoulos S, Griffin RJ, Aherne GW, Raynaud FI, Workman P, Jones K, van Montfort RL. The discovery of potent ribosomal S6 kinase inhibitors by high-throughput screening and structure-guided drug design. Oncotarget. 2013 Aug 25. PMID:24072592

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4c38"

@@ Line 1: / Line 1: @@
 ==PKA-S6K1 Chimera with compound 21e (CCT239066) bound==
 <StructureSection load='4c38' size='340' side='right' caption='[[4c38]], [[Resolution|resolution]] 1.58&Aring;' scene=''>
@@ Line 7: / Line 8: @@
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c33|4c33]], [[4c34|4c34]], [[4c35|4c35]], [[4c36|4c36]], [[4c37|4c37]]</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/cAMP-dependent_protein_kinase cAMP-dependent protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.11 2.7.11.11] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c38 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c38 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4c38 RCSB], [http://www.ebi.ac.uk/pdbsum/4c38 PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4c38 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c38 OCA], [http://pdbe.org/4c38 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4c38 RCSB], [http://www.ebi.ac.uk/pdbsum/4c38 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4c38 ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 19: / Line 20: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 4c38" style="background-color:#fffaf0;"></div>
 ==See Also==

4c38

From Proteopedia

Revision as of 21:16, 4 August 2016

PKA-S6K1 Chimera with compound 21e (CCT239066) bound

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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