This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.

Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.

4axa

From Proteopedia

(Difference between revisions)

Jump to: navigation, search

Revision as of 07:24, 4 August 2016

Structure of PKA-PKB chimera complexed with (1S)-2-amino-1-(4- chlorophenyl)-1-(4-(1H-pyrazol-4-yl)phenyl)ethan-1-ol

Structural highlights

4axa 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:	1cmk, 1jlu, 1kmu, 1kmw, 1q24, 1q61, 1q62, 1q8t, 1q8u, 1q8w, 1smh, 1stc, 1sve, 1svg, 1svh, 1szm, 1veb, 1xh4, 1xh5, 1xh6, 1xh7, 1xh8, 1xh9, 1xha, 1ydr, 1yds, 1ydt, 2c1a, 2c1b, 2f7e, 2gfc, 2gnf, 2gng, 2gnh, 2gni, 2gnj, 2gnl, 2jds, 2jdt, 2jdv, 2uvx, 2uvy, 2uvz, 2uw0, 2uw3, 2uw4, 2uw5, 2uw6, 2uw7, 2uw8, 2uzt, 2uzu, 2uzv, 2uzw, 2vnw, 2vny, 2vo0, 2vo3, 2vo6, 2vo7
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). [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.

Publication Abstract from PubMed

PURPOSE: Deregulated phosphatidylinositol 3-kinase pathway signaling through AGC kinases including AKT, p70S6 kinase, PKA, SGK and Rho kinase is a key driver of multiple cancers. The simultaneous inhibition of multiple AGC kinases may increase antitumor activity and minimize clinical resistance compared with a single pathway component. EXPERIMENTAL DESIGN: We investigated the detailed pharmacology and antitumor activity of the novel clinical drug candidate AT13148, an oral ATP-competitive multi-AGC kinase inhibitor. Gene expression microarray studies were undertaken to characterize the molecular mechanisms of action of AT13148. RESULTS: AT13148 caused substantial blockade of AKT, p70S6K, PKA, ROCK, and SGK substrate phosphorylation and induced apoptosis in a concentration and time-dependent manner in cancer cells with clinically relevant genetic defects in vitro and in vivo. Antitumor efficacy in HER2-positive, PIK3CA-mutant BT474 breast, PTEN-deficient PC3 human prostate cancer, and PTEN-deficient MES-SA uterine tumor xenografts was shown. We show for the first time that induction of AKT phosphorylation at serine 473 by AT13148, as reported for other ATP-competitive inhibitors of AKT, is not a therapeutically relevant reactivation step. Gene expression studies showed that AT13148 has a predominant effect on apoptosis genes, whereas the selective AKT inhibitor CCT128930 modulates cell-cycle genes. Induction of upstream regulators including IRS2 and PIK3IP1 as a result of compensatory feedback loops was observed. CONCLUSIONS: The clinical candidate AT13148 is a novel oral multi-AGC kinase inhibitor with potent pharmacodynamic and antitumor activity, which shows a distinct mechanism of action from other AKT inhibitors. AT13148 will now be assessed in a first-in-human phase I trial. Clin Cancer Res; 18(14); 3912-23. (c)2012 AACR.

AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity.,Yap TA, Walton MI, Grimshaw KM, Te Poele RH, Eve PD, Valenti MR, de Haven Brandon AK, Martins V, Zetterlund A, Heaton SP, Heinzmann K, Jones PS, Feltell RE, Reule M, Woodhead SJ, Davies TG, Lyons JF, Raynaud FI, Eccles SA, Workman P, Thompson NT, Garrett MD Clin Cancer Res. 2012 Jul 15;18(14):3912-23. Epub 2012 Jul 10. PMID:22781553^[1]

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

References

↑ Yap TA, Walton MI, Grimshaw KM, Te Poele RH, Eve PD, Valenti MR, de Haven Brandon AK, Martins V, Zetterlund A, Heaton SP, Heinzmann K, Jones PS, Feltell RE, Reule M, Woodhead SJ, Davies TG, Lyons JF, Raynaud FI, Eccles SA, Workman P, Thompson NT, Garrett MD. AT13148 Is a Novel, Oral Multi-AGC Kinase Inhibitor with Potent Pharmacodynamic and Antitumor Activity. Clin Cancer Res. 2012 Jul 15;18(14):3912-23. Epub 2012 Jul 10. PMID:22781553 doi:10.1158/1078-0432.CCR-11-3313

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/4axa"

@@ Line 1: / Line 1: @@
 ==Structure of PKA-PKB chimera complexed with (1S)-2-amino-1-(4- chlorophenyl)-1-(4-(1H-pyrazol-4-yl)phenyl)ethan-1-ol==
 <StructureSection load='4axa' size='340' side='right' caption='[[4axa]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4axa]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bos_taurus Bos taurus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AXA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4AXA FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4axa]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Bovin Bovin]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4AXA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4AXA FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=RKD:(2S)-2-(4-CHLOROPHENYL)-2-HYDROXY-2-[4-(1H-PYRAZOL-4-YL)PHENYL]ETHANAMINIUM'>RKD</scene></td></tr>
 <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=SEP:PHOSPHOSERINE'>SEP</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1cmk|1cmk]], [[1jlu|1jlu]], [[1kmu|1kmu]], [[1kmw|1kmw]], [[1q24|1q24]], [[1q61|1q61]], [[1q62|1q62]], [[1q8t|1q8t]], [[1q8u|1q8u]], [[1q8w|1q8w]], [[1smh|1smh]], [[1stc|1stc]], [[1sve|1sve]], [[1svg|1svg]], [[1svh|1svh]], [[1szm|1szm]], [[1veb|1veb]], [[1xh4|1xh4]], [[1xh5|1xh5]], [[1xh6|1xh6]], [[1xh7|1xh7]], [[1xh8|1xh8]], [[1xh9|1xh9]], [[1xha|1xha]], [[1ydr|1ydr]], [[1yds|1yds]], [[1ydt|1ydt]], [[2c1a|2c1a]], [[2c1b|2c1b]], [[2f7e|2f7e]], [[2gfc|2gfc]], [[2gnf|2gnf]], [[2gng|2gng]], [[2gnh|2gnh]], [[2gni|2gni]], [[2gnj|2gnj]], [[2gnl|2gnl]], [[2jds|2jds]], [[2jdt|2jdt]], [[2jdv|2jdv]], [[2uvx|2uvx]], [[2uvy|2uvy]], [[2uvz|2uvz]], [[2uw0|2uw0]], [[2uw3|2uw3]], [[2uw4|2uw4]], [[2uw5|2uw5]], [[2uw6|2uw6]], [[2uw7|2uw7]], [[2uw8|2uw8]], [[2uzt|2uzt]], [[2uzu|2uzu]], [[2uzv|2uzv]], [[2uzw|2uzw]], [[2vnw|2vnw]], [[2vny|2vny]], [[2vo0|2vo0]], [[2vo3|2vo3]], [[2vo6|2vo6]], [[2vo7|2vo7]]</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=4axa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4axa OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4axa RCSB], [http://www.ebi.ac.uk/pdbsum/4axa 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=4axa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4axa OCA], [http://pdbe.org/4axa PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4axa RCSB], [http://www.ebi.ac.uk/pdbsum/4axa PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4axa 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 4axa" style="background-color:#fffaf0;"></div>
 ==See Also==
@@ Line 26: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Bos taurus]]
+[[Category: Bovin]]
 [[Category: CAMP-dependent protein kinase]]
 [[Category: Davies, T G]]

4axa

From Proteopedia

Revision as of 07:24, 4 August 2016

Structure of PKA-PKB chimera complexed with (1S)-2-amino-1-(4- chlorophenyl)-1-(4-(1H-pyrazol-4-yl)phenyl)ethan-1-ol

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

Personal tools

Navigation

Search

Toolbox