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2bts

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[[Image:2bts.gif|left|200px]]<br /><applet load="2bts" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="2bts, resolution 1.99&Aring;" />
 
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'''STRUCTURE OF CDK2 COMPLEXED WITH PNU-230032'''<br />
 
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==Overview==
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==STRUCTURE OF CDK2 COMPLEXED WITH PNU-230032==
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N-(5-Bromo-1,3-thiazol-2-yl)butanamide (compound 1) was found active, (IC50=808 nM) in a high throughput screening (HTS) for CDK2 inhibitors. By, exploiting crystal structures of several complexes between CDK2 and, inhibitors and applying structure-based drug design (SBDD), we rapidly, discovered a very potent and selective CDK2 inhibitor, 4-[(5-isopropyl-1,3-thiazol-2-yl)amino] benzenesulfonamide (compound 4, IC50=20 nM). The syntheses, structure-based analog design, kinases, inhibition data and X-ray crystallographic structures of CDK2/inhibitor, complexes are reported.
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<StructureSection load='2bts' size='340' side='right'caption='[[2bts]], [[Resolution|resolution]] 1.99&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[2bts]] 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=2BTS OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2BTS 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]] 1.99&#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=U32:4-[(5-ISOPROPYL-1,3-THIAZOL-2-YL)AMINO]BENZENESULFONAMIDE'>U32</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=2bts FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2bts OCA], [https://pdbe.org/2bts PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2bts RCSB], [https://www.ebi.ac.uk/pdbsum/2bts PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2bts ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/CDK2_HUMAN CDK2_HUMAN] Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Interacts with cyclins A, B1, B3, D, or E. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization.<ref>PMID:10499802</ref> <ref>PMID:11051553</ref> <ref>PMID:10995386</ref> <ref>PMID:10995387</ref> <ref>PMID:10884347</ref> <ref>PMID:11113184</ref> <ref>PMID:15800615</ref> <ref>PMID:18372919</ref> <ref>PMID:20147522</ref> <ref>PMID:20079829</ref> <ref>PMID:20935635</ref> <ref>PMID:20195506</ref> <ref>PMID:19966300</ref> <ref>PMID:21262353</ref> <ref>PMID:21596315</ref> <ref>PMID:21319273</ref> <ref>PMID:17495531</ref>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/bt/2bts_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2bts ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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N-(5-Bromo-1,3-thiazol-2-yl)butanamide (compound 1) was found active (IC50=808 nM) in a high throughput screening (HTS) for CDK2 inhibitors. By exploiting crystal structures of several complexes between CDK2 and inhibitors and applying structure-based drug design (SBDD), we rapidly discovered a very potent and selective CDK2 inhibitor 4-[(5-isopropyl-1,3-thiazol-2-yl)amino] benzenesulfonamide (compound 4, IC50=20 nM). The syntheses, structure-based analog design, kinases inhibition data and X-ray crystallographic structures of CDK2/inhibitor complexes are reported.
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==About this Structure==
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Structure-based drug design to the discovery of new 2-aminothiazole CDK2 inhibitors.,Vulpetti A, Casale E, Roletto F, Amici R, Villa M, Pevarello P J Mol Graph Model. 2006 Mar;24(5):341-8. Epub 2005 Nov 2. PMID:16260160<ref>PMID:16260160</ref>
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2BTS is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with U32 as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [http://en.wikipedia.org/wiki/Transferred_entry:_2.7.11.1 Transferred entry: 2.7.11.1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.37 2.7.1.37] Known structural/functional Site: <scene name='pdbsite=AC1:U32 Binding Site For Chain A'>AC1</scene>. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2BTS OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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Structure-based drug design to the discovery of new 2-aminothiazole CDK2 inhibitors., Vulpetti A, Casale E, Roletto F, Amici R, Villa M, Pevarello P, J Mol Graph Model. 2006 Mar;24(5):341-8. Epub 2005 Nov 2. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16260160 16260160]
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</div>
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[[Category: Homo sapiens]]
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<div class="pdbe-citations 2bts" style="background-color:#fffaf0;"></div>
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[[Category: Single protein]]
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[[Category: Transferred entry: 2.7.11.1]]
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[[Category: Amici, R.]]
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[[Category: Casale, E.]]
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[[Category: Pevarello, P.]]
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[[Category: Roletto, F.]]
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[[Category: Villa, M.]]
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[[Category: Vulpetti, A.]]
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[[Category: U32]]
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[[Category: atp-binding]]
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[[Category: cell cycle]]
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[[Category: cell division]]
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[[Category: mitosis]]
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[[Category: phosphorylation]]
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[[Category: polymorphism]]
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[[Category: protein kinase]]
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[[Category: serine/threonine-protein 2 kinase]]
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[[Category: transferase]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Tue Dec 18 18:58:18 2007''
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==See Also==
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*[[Cyclin-dependent kinase 3D structures|Cyclin-dependent kinase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Amici R]]
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[[Category: Casale E]]
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[[Category: Pevarello P]]
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[[Category: Roletto F]]
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[[Category: Villa M]]
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[[Category: Vulpetti A]]

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STRUCTURE OF CDK2 COMPLEXED WITH PNU-230032

PDB ID 2bts

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