4bch

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<StructureSection load='4bch' size='340' side='right'caption='[[4bch]], [[Resolution|resolution]] 2.96&Aring;' scene=''>
<StructureSection load='4bch' size='340' side='right'caption='[[4bch]], [[Resolution|resolution]] 2.96&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4bch]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BCH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BCH FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4bch]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4BCH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BCH FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=T7Z:4-(4-METHYL-2-METHYLIMINO-3H-1,3-THIAZOL-5-YL)-2-[(4-METHYL-3-MORPHOLIN-4-YLSULFONYL-PHENYL)AMINO]PYRIMIDINE-5-CARBONITRILE'>T7Z</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.958&#8491;</td></tr>
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<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=T7Z:4-(4-METHYL-2-METHYLIMINO-3H-1,3-THIAZOL-5-YL)-2-[(4-METHYL-3-MORPHOLIN-4-YLSULFONYL-PHENYL)AMINO]PYRIMIDINE-5-CARBONITRILE'>T7Z</scene>, <scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1pf6|1pf6]], [[4bcf|4bcf]], [[4bcg|4bcg]], [[4bci|4bci]], [[4bcj|4bcj]], [[4bck|4bck]], [[4bcm|4bcm]], [[4bcn|4bcn]], [[4bco|4bco]], [[4bcp|4bcp]], [[4bcq|4bcq]]</div></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4bch FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bch OCA], [https://pdbe.org/4bch PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bch RCSB], [https://www.ebi.ac.uk/pdbsum/4bch PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bch 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=4bch FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bch OCA], [https://pdbe.org/4bch PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bch RCSB], [https://www.ebi.ac.uk/pdbsum/4bch PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bch ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[https://www.uniprot.org/uniprot/CDK9_HUMAN CDK9_HUMAN]] Note=Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy, and confers predisposition to heart failure.
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[https://www.uniprot.org/uniprot/CDK9_HUMAN CDK9_HUMAN] Note=Chronic activation of CDK9 causes cardiac myocyte enlargement leading to cardiac hypertrophy, and confers predisposition to heart failure.
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/CDK9_HUMAN CDK9_HUMAN]] Protein kinase involved in the regulation of transcription. Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR, and the negative elongation factors DSIF and NELF. Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing. The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro. Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single-stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation.<ref>PMID:9857195</ref> <ref>PMID:10393184</ref> <ref>PMID:10574912</ref> <ref>PMID:10912001</ref> <ref>PMID:10757782</ref> <ref>PMID:11145967</ref> <ref>PMID:11112772</ref> <ref>PMID:11575923</ref> <ref>PMID:11884399</ref> <ref>PMID:11809800</ref> <ref>PMID:12037670</ref> <ref>PMID:15564463</ref> <ref>PMID:14701750</ref> <ref>PMID:17956865</ref> <ref>PMID:18362169</ref> <ref>PMID:19844166</ref> <ref>PMID:19575011</ref> <ref>PMID:20493174</ref> <ref>PMID:20930849</ref> <ref>PMID:20081228</ref> <ref>PMID:20980437</ref> <ref>PMID:21127351</ref> [[https://www.uniprot.org/uniprot/CCNT1_HUMAN CCNT1_HUMAN]] Regulatory subunit of the cyclin-dependent kinase pair (CDK9/cyclin-T1) complex, also called positive transcription elongation factor B (P-TEFb), which is proposed to facilitate the transition from abortive to productive elongation by phosphorylating the CTD (carboxy-terminal domain) of the large subunit of RNA polymerase II (RNA Pol II). In case of HIV or SIV infections, binds to the transactivation domain of the viral nuclear transcriptional activator, Tat, thereby increasing Tat's affinity for the transactivating response RNA element (TAR RNA). Serves as an essential cofactor for Tat, by promoting RNA Pol II activation, allowing transcription of viral genes.
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[https://www.uniprot.org/uniprot/CDK9_HUMAN CDK9_HUMAN] Protein kinase involved in the regulation of transcription. Member of the cyclin-dependent kinase pair (CDK9/cyclin-T) complex, also called positive transcription elongation factor b (P-TEFb), which facilitates the transition from abortive to productive elongation by phosphorylating the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAP II) POLR2A, SUPT5H and RDBP. This complex is inactive when in the 7SK snRNP complex form. Phosphorylates EP300, MYOD1, RPB1/POLR2A and AR, and the negative elongation factors DSIF and NELF. Regulates cytokine inducible transcription networks by facilitating promoter recognition of target transcription factors (e.g. TNF-inducible RELA/p65 activation and IL-6-inducible STAT3 signaling). Promotes RNA synthesis in genetic programs for cell growth, differentiation and viral pathogenesis. P-TEFb is also involved in cotranscriptional histone modification, mRNA processing and mRNA export. Modulates a complex network of chromatin modifications including histone H2B monoubiquitination (H2Bub1), H3 lysine 4 trimethylation (H3K4me3) and H3K36me3; integrates phosphorylation during transcription with chromatin modifications to control co-transcriptional histone mRNA processing. The CDK9/cyclin-K complex has also a kinase activity towards CTD of RNAP II and can substitute for CDK9/cyclin-T P-TEFb in vitro. Replication stress response protein; the CDK9/cyclin-K complex is required for genome integrity maintenance, by promoting cell cycle recovery from replication arrest and limiting single-stranded DNA amount in response to replication stress, thus reducing the breakdown of stalled replication forks and avoiding DNA damage. In addition, probable function in DNA repair of isoform 2 via interaction with KU70/XRCC6. Promotes cardiac myocyte enlargement. RPB1/POLR2A phosphorylation on 'Ser-2' in CTD activates transcription. AR phosphorylation modulates AR transcription factor promoter selectivity and cell growth. DSIF and NELF phosphorylation promotes transcription by inhibiting their negative effect. The phosphorylation of MYOD1 enhances its transcriptional activity and thus promotes muscle differentiation.<ref>PMID:9857195</ref> <ref>PMID:10393184</ref> <ref>PMID:10574912</ref> <ref>PMID:10912001</ref> <ref>PMID:10757782</ref> <ref>PMID:11145967</ref> <ref>PMID:11112772</ref> <ref>PMID:11575923</ref> <ref>PMID:11884399</ref> <ref>PMID:11809800</ref> <ref>PMID:12037670</ref> <ref>PMID:15564463</ref> <ref>PMID:14701750</ref> <ref>PMID:17956865</ref> <ref>PMID:18362169</ref> <ref>PMID:19844166</ref> <ref>PMID:19575011</ref> <ref>PMID:20493174</ref> <ref>PMID:20930849</ref> <ref>PMID:20081228</ref> <ref>PMID:20980437</ref> <ref>PMID:21127351</ref>
<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>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Baumli, S]]
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[[Category: Baumli S]]
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[[Category: Endicott, J A]]
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[[Category: Endicott JA]]
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[[Category: Hole, A J]]
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[[Category: Hole AJ]]
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[[Category: Noble, M E.M]]
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[[Category: Noble MEM]]
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[[Category: Wang, S]]
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[[Category: Wang S]]
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[[Category: Cdk-cyclin complex]]
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[[Category: Structure-based drug design]]
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[[Category: Transcription-protein binding]]
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[[Category: Transferase-cell cycle complex]]
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Current revision

Structure of CDK9 in complex with cyclin T and a 2-amino-4-heteroaryl- pyrimidine inhibitor

PDB ID 4bch

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