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4au8

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{{STRUCTURE_4au8| PDB=4au8 | SCENE= }}
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==Crystal structure of compound 4a in complex with cdk5, showing an unusual binding mode to the hinge region via a water molecule==
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===Crystal structure of compound 4a in complex with cdk5, showing an unusual binding mode to the hinge region via a water molecule===
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<StructureSection load='4au8' size='340' side='right' caption='[[4au8]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
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{{ABSTRACT_PUBMED_22889803}}
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== Structural highlights ==
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<table><tr><td colspan='2'>[[4au8]] is a 2 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=4AU8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4AU8 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=IMD:IMIDAZOLE'>IMD</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=Z3R:4-(1,3-BENZOTHIAZOL-2-YL)THIOPHENE-2-SULFONAMIDE'>Z3R</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1h4l|1h4l]], [[1lfr|1lfr]], [[1ung|1ung]], [[1unh|1unh]], [[1unl|1unl]]</td></tr>
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<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Cyclin-dependent_kinase Cyclin-dependent kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.22 2.7.11.22] </span></td></tr>
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<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=4au8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4au8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4au8 RCSB], [http://www.ebi.ac.uk/pdbsum/4au8 PDBsum]</span></td></tr>
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</table>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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4-(1,3-Benzothiazol-2-yl)thiophene-2-sulfonamide (4a) was found to be a moderately potent inhibitor of cyclin-dependent kinase 5 (cdk5) from a HTS screen. The synthesis and SAR around this hit is described. The X-ray coordinates of ligand 4a with cdk5 are also reported, showing an unusual binding mode to the hinge region via a water molecule.
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==Function==
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Synthesis and structure-activity relationship of 4-(1,3-benzothiazol-2-yl)-thiophene-2-sulfonamides as cyclin-dependent kinase 5 (cdk5)/p25 inhibitors.,Malmstrom J, Viklund J, Slivo C, Costa A, Maudet M, Sandelin C, Hiller G, Olsson LL, Aagaard A, Geschwindner S, Xue Y, Vasange M Bioorg Med Chem Lett. 2012 Sep 15;22(18):5919-23. doi:, 10.1016/j.bmcl.2012.07.068. Epub 2012 Jul 25. PMID:22889803<ref>PMID:22889803</ref>
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[[http://www.uniprot.org/uniprot/CDK5_HUMAN CDK5_HUMAN]] Proline-directed serine/threonine-protein kinase essential for neuronal cell cycle arrest and differentiation and may be involved in apoptotic cell death in neuronal diseases by triggering abortive cell cycle re-entry. Interacts with D1 and D3-type G1 cyclins. Phosphorylates SRC, NOS3, VIM/vimentin, p35/CDK5R1, MEF2A, SIPA1L1, SH3GLB1, PXN, PAK1, MCAM/MUC18, SEPT5, SYN1, DNM1, AMPH, SYNJ1, CDK16, RAC1, RHOA, CDC42, TONEBP/NFAT5, MAPT/TAU, MAP1B, histone H1, p53/TP53, HDAC1, APEX1, PTK2/FAK1, huntingtin/HTT, ATM, MAP2, NEFH and NEFM. Regulates several neuronal development and physiological processes including neuronal survival, migration and differentiation, axonal and neurite growth, synaptogenesis, oligodendrocyte differentiation, synaptic plasticity and neurotransmission, by phosphorylating key proteins. Activated by interaction with CDK5R1 (p35) and ATP6V0D1 (p39), especially in post-mitotic neurons, and promotes CDK5R1 (p35) expression in an autostimulation loop. Phosphorylates many downstream substrates such as Rho and Ras family small GTPases (e.g. PAK1, RAC1, RHOA, CDC42) or microtubule-binding proteins (e.g. MAPT/TAU, MAP2, MAP1B), and modulates actin dynamics to regulate neurite growth and/or spine morphogenesis. Phosphorylates also exocytosis associated proteins such as MCAM/MUC18, SEPT5, SYN1, and CDK16/PCTAIRE1 as well as endocytosis associated proteins such as DNM1, AMPH and SYNJ1 at synaptic terminals. In the mature central nervous system (CNS), regulates neurotransmitter movements by phosphorylating substrates associated with neurotransmitter release and synapse plasticity; synaptic vesicle exocytosis, vesicles fusion with the presynaptic membrane, and endocytosis. Promotes cell survival by activating anti-apoptotic proteins BCL2 and STAT3, and negatively regulating of JNK3/MAPK10 activity. Phosphorylation of p53/TP53 in response to genotoxic and oxidative stresses enhances its stabilization by preventing ubiquitin ligase-mediated proteasomal degradation, and induces transactivation of p53/TP53 target genes, thus regulating apoptosis. Phosphorylation of p35/CDK5R1 enhances its stabilization by preventing calpain-mediated proteolysis producing p25/CDK5R1 and avoiding ubiquitin ligase-mediated proteasomal degradation. During aberrant cell-cycle activity and DNA damage, p25/CDK5 activity elicits cell-cycle activity and double-strand DNA breaks that precedes neuronal death by deregulating HDAC1. DNA damage triggered phosphorylation of huntingtin/HTT in nuclei of neurons protects neurons against polyglutamine expansion as well as DNA damage mediated toxicity. Phosphorylation of PXN reduces its interaction with PTK2/FAK1 in matrix-cell focal adhesions (MCFA) during oligodendrocytes (OLs) differentiation. Negative regulator of Wnt/beta-catenin signaling pathway. Activator of the GAIT (IFN-gamma-activated inhibitor of translation) pathway, which suppresses expression of a post-transcriptional regulon of proinflammatory genes in myeloid cells; phosphorylates the linker domain of glutamyl-prolyl tRNA synthetase (EPRS) in a IFN-gamma-dependent manner, the initial event in assembly of the GAIT complex. Phosphorylation of SH3GLB1 is required for autophagy induction in starved neurons. Phosphorylation of TONEBP/NFAT5 in response to osmotic stress mediates its rapid nuclear localization. MEF2 is inactivated by phosphorylation in nucleus in response to neurotoxin, thus leading to neuronal apoptosis. APEX1 AP-endodeoxyribonuclease is repressed by phosphorylation, resulting in accumulation of DNA damage and contributing to neuronal death. NOS3 phosphorylation down regulates NOS3-derived nitrite (NO) levels. SRC phosphorylation mediates its ubiquitin-dependent degradation and thus leads to cytoskeletal reorganization. May regulate endothelial cell migration and angiogenesis via the modulation of lamellipodia formation. Involved in dendritic spine morphogenesis by mediating the EFNA1-EPHA4 signaling.<ref>PMID:19693690</ref><ref>PMID:9822744</ref><ref>PMID:12393264</ref><ref>PMID:12691662</ref><ref>PMID:15992363</ref><ref>PMID:17121855</ref><ref>PMID:17009320</ref><ref>PMID:17591690</ref><ref>PMID:18042622</ref><ref>PMID:17611284</ref><ref>PMID:17671990</ref><ref>PMID:19081376</ref><ref>PMID:20826806</ref><ref>PMID:20213743</ref><ref>PMID:21442427</ref><ref>PMID:21465480</ref><ref>PMID:21209322</ref><ref>PMID:21499257</ref><ref>PMID:21220307</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[4au8]] is a 2 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=4AU8 OCA].
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</div>
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== References ==
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==Reference==
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<references/>
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<references group="xtra"/><references/>
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__TOC__
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</StructureSection>
[[Category: Cyclin-dependent kinase]]
[[Category: Cyclin-dependent kinase]]
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Aagaard, A.]]
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[[Category: Aagaard, A]]
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[[Category: Costa, A.]]
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[[Category: Costa, A]]
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[[Category: Geschwindner, S.]]
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[[Category: Geschwindner, S]]
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[[Category: Hiller, G.]]
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[[Category: Hiller, G]]
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[[Category: Malmstrom, J.]]
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[[Category: Malmstrom, J]]
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[[Category: Maudet, M.]]
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[[Category: Maudet, M]]
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[[Category: Olsson, L L.]]
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[[Category: Olsson, L L]]
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[[Category: Sandelin, C.]]
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[[Category: Sandelin, C]]
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[[Category: Slivo, C.]]
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[[Category: Slivo, C]]
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[[Category: Vasange, M.]]
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[[Category: Vasange, M]]
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[[Category: Viklund, J.]]
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[[Category: Viklund, J]]
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[[Category: Xue, Y.]]
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[[Category: Xue, Y]]
[[Category: Alzheimer disease]]
[[Category: Alzheimer disease]]
[[Category: Cdk2]]
[[Category: Cdk2]]
[[Category: Transferase]]
[[Category: Transferase]]

Revision as of 09:55, 21 December 2014

Crystal structure of compound 4a in complex with cdk5, showing an unusual binding mode to the hinge region via a water molecule

4au8, resolution 1.90Å

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