3ot3

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[[Image:3ot3.png|left|200px]]
 
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{{STRUCTURE_3ot3| PDB=3ot3 | SCENE= }}
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==X-ray crystal structure of compound 22k bound to human Chk1 kinase domain==
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<StructureSection load='3ot3' size='340' side='right'caption='[[3ot3]], [[Resolution|resolution]] 1.44&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3ot3]] is a 1 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=3OT3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OT3 FirstGlance]. <br>
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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]] 1.44&#8491;</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=22K:5-[(1R,3S)-3-AMINOCYCLOHEXYL]-6-BROMO-3-(1-METHYL-1H-PYRAZOL-4-YL)PYRAZOLO[1,5-A]PYRIMIDIN-7-AMINE'>22K</scene></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=3ot3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ot3 OCA], [https://pdbe.org/3ot3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ot3 RCSB], [https://www.ebi.ac.uk/pdbsum/3ot3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ot3 ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/CHK1_HUMAN CHK1_HUMAN] Serine/threonine-protein kinase which is required for checkpoint-mediated cell cycle arrest and activation of DNA repair in response to the presence of DNA damage or unreplicated DNA. May also negatively regulate cell cycle progression during unperturbed cell cycles. This regulation is achieved by a number of mechanisms that together help to preserve the integrity of the genome. Recognizes the substrate consensus sequence [R-X-X-S/T]. Binds to and phosphorylates CDC25A, CDC25B and CDC25C. Phosphorylation of CDC25A at 'Ser-178' and 'Thr-507' and phosphorylation of CDC25C at 'Ser-216' creates binding sites for 14-3-3 proteins which inhibit CDC25A and CDC25C. Phosphorylation of CDC25A at 'Ser-76', 'Ser-124', 'Ser-178', 'Ser-279' and 'Ser-293' promotes proteolysis of CDC25A. Phosphorylation of CDC25A at 'Ser-76' primes the protein for subsequent phosphorylation at 'Ser-79', 'Ser-82' and 'Ser-88' by NEK11, which is required for polyubiquitination and degradation of CDCD25A. Inhibition of CDC25 leads to increased inhibitory tyrosine phosphorylation of CDK-cyclin complexes and blocks cell cycle progression. Also phosphorylates NEK6. Binds to and phosphorylates RAD51 at 'Thr-309', which promotes the release of RAD51 from BRCA2 and enhances the association of RAD51 with chromatin, thereby promoting DNA repair by homologous recombination. Phosphorylates multiple sites within the C-terminus of TP53, which promotes activation of TP53 by acetylation and promotes cell cycle arrest and suppression of cellular proliferation. Also promotes repair of DNA cross-links through phosphorylation of FANCE. Binds to and phosphorylates TLK1 at 'Ser-743', which prevents the TLK1-dependent phosphorylation of the chromatin assembly factor ASF1A. This may enhance chromatin assembly both in the presence or absence of DNA damage. May also play a role in replication fork maintenance through regulation of PCNA. May regulate the transcription of genes that regulate cell-cycle progression through the phosphorylation of histones. Phosphorylates histone H3.1 (to form H3T11ph), which leads to epigenetic inhibition of a subset of genes. May also phosphorylate RB1 to promote its interaction with the E2F family of transcription factors and subsequent cell cycle arrest.<ref>PMID:9278511</ref> <ref>PMID:10673501</ref> <ref>PMID:11535615</ref> <ref>PMID:12446774</ref> <ref>PMID:12399544</ref> <ref>PMID:12676583</ref> <ref>PMID:12660173</ref> <ref>PMID:14681206</ref> <ref>PMID:12676925</ref> <ref>PMID:12759351</ref> <ref>PMID:14559997</ref> <ref>PMID:14988723</ref> <ref>PMID:15311285</ref> <ref>PMID:15659650</ref> <ref>PMID:15665856</ref> <ref>PMID:15650047</ref> <ref>PMID:16511572</ref> <ref>PMID:16963448</ref> <ref>PMID:17380128</ref> <ref>PMID:17296736</ref> <ref>PMID:18510930</ref> <ref>PMID:18728393</ref> <ref>PMID:18451105</ref> <ref>PMID:18317453</ref> <ref>PMID:19734889</ref> <ref>PMID:20090422</ref> Isoform 2: Endogenous repressor of isoform 1, interacts with, and antagonizes CHK1 to promote the S to G2/M phase transition.<ref>PMID:9278511</ref> <ref>PMID:10673501</ref> <ref>PMID:11535615</ref> <ref>PMID:12446774</ref> <ref>PMID:12399544</ref> <ref>PMID:12676583</ref> <ref>PMID:12660173</ref> <ref>PMID:14681206</ref> <ref>PMID:12676925</ref> <ref>PMID:12759351</ref> <ref>PMID:14559997</ref> <ref>PMID:14988723</ref> <ref>PMID:15311285</ref> <ref>PMID:15659650</ref> <ref>PMID:15665856</ref> <ref>PMID:15650047</ref> <ref>PMID:16511572</ref> <ref>PMID:16963448</ref> <ref>PMID:17380128</ref> <ref>PMID:17296736</ref> <ref>PMID:18510930</ref> <ref>PMID:18728393</ref> <ref>PMID:18451105</ref> <ref>PMID:18317453</ref> <ref>PMID:19734889</ref> <ref>PMID:20090422</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Previous efforts by our group have established pyrazolo[1,5-a]pyrimidine as a viable core for the development of potent and selective CDK inhibitors. As part of an effort to utilize the pyrazolo[1,5-a]pyrimidine core as a template for the design and synthesis of potent and selective kinase inhibitors, we focused on a key regulator in the cell cycle progression, CHK1. Continued SAR development of the pyrazolo[1,5-a]pyrimidine core at the C5 and C6 positions, in conjunction with previously disclosed SAR at the C3 and C7 positions, led to the discovery of potent and selective CHK1 inhibitors.
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===X-ray crystal structure of compound 22k bound to human Chk1 kinase domain===
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Discovery of pyrazolo[1,5-a]pyrimidine-based CHK1 inhibitors: A template-based approach-Part 2.,Labroli M, Paruch K, Dwyer MP, Alvarez C, Keertikar K, Poker C, Rossman R, Duca JS, Fischmann TO, Madison V, Parry D, Davis N, Seghezzi W, Wiswell D, Guzi TJ Bioorg Med Chem Lett. 2010 Oct 28. PMID:21094607<ref>PMID:21094607</ref>
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{{ABSTRACT_PUBMED_21094607}}
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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==About this Structure==
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<div class="pdbe-citations 3ot3" style="background-color:#fffaf0;"></div>
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[[3ot3]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OT3 OCA].
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==See Also==
==See Also==
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*[[Serine/threonine protein kinase|Serine/threonine protein kinase]]
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*[[Serine/threonine protein kinase 3D structures|Serine/threonine protein kinase 3D structures]]
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== References ==
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==Reference==
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<references/>
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<ref group="xtra">PMID:021094607</ref><references group="xtra"/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Non-specific serine/threonine protein kinase]]
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[[Category: Large Structures]]
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[[Category: Fischmann, T O.]]
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[[Category: Fischmann TO]]
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[[Category: Kinase]]
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[[Category: Phosphatase]]
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[[Category: Transferase-transferase inhibitor complex]]
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Current revision

X-ray crystal structure of compound 22k bound to human Chk1 kinase domain

PDB ID 3ot3

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