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[[ | ==PDE10a Crystal Structure Complexed with Novel Inhibitor== | ||
<StructureSection load='4ddl' size='340' side='right' caption='[[4ddl]], [[Resolution|resolution]] 2.07Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4ddl]] 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=4DDL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DDL FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0JQ:2-{1-[5-(6,7-DIMETHOXYCINNOLIN-4-YL)-3-METHYLPYRIDIN-2-YL]PIPERIDIN-4-YL}PROPAN-2-OL'>0JQ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2oup|2oup]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE10A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4ddl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ddl OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4ddl RCSB], [http://www.ebi.ac.uk/pdbsum/4ddl PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/PDE10_HUMAN PDE10_HUMAN]] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.<ref>PMID:17389385</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
We report the discovery of 6,7-dimethoxy-4-(pyridin-3-yl)cinnolines as novel inhibitors of phosphodiesterase 10A (PDE10A). Systematic examination and analyses of structure-activity-relationships resulted in single digit nM potency against PDE10A. X-ray co-crystal structure revealed the mode of binding in the enzyme's catalytic domain and the source of selectivity against other PDEs. High in vivo clearance in rats was addressed with the help of metabolite identification (ID) studies. These findings combined resulted in compound 39, a promising potent inhibitor of PDE10A with good in vivo metabolic stability in rats and efficacy in a rodent behavioral model. | |||
Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodiesterase 10A (PDE10A) inhibitors.,Hu E, Kunz RK, Rumfelt S, Chen N, Burli R, Li C, Andrews KL, Zhang J, Chmait S, Kogan J, Lindstrom M, Hitchcock SA, Treanor J Bioorg Med Chem Lett. 2012 Mar 15;22(6):2262-5. Epub 2012 Feb 8. PMID:22365755<ref>PMID:22365755</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | |||
*[[Phosphodiesterase|Phosphodiesterase]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
[[ | |||
== | |||
< | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Chmait, S | [[Category: Chmait, S]] | ||
[[Category: Jordan, S | [[Category: Jordan, S]] | ||
[[Category: Zhang, J | [[Category: Zhang, J]] | ||
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
[[Category: Phosphodiesterase 10a]] | [[Category: Phosphodiesterase 10a]] | ||
Revision as of 11:16, 25 December 2014
PDE10a Crystal Structure Complexed with Novel InhibitorPDE10a Crystal Structure Complexed with Novel Inhibitor
Structural highlights
Function[PDE10_HUMAN] Plays a role in signal transduction by regulating the intracellular concentration of cyclic nucleotides. Can hydrolyze both cAMP and cGMP, but has higher affinity for cAMP and is more efficient with cAMP as substrate.[1] Publication Abstract from PubMedWe report the discovery of 6,7-dimethoxy-4-(pyridin-3-yl)cinnolines as novel inhibitors of phosphodiesterase 10A (PDE10A). Systematic examination and analyses of structure-activity-relationships resulted in single digit nM potency against PDE10A. X-ray co-crystal structure revealed the mode of binding in the enzyme's catalytic domain and the source of selectivity against other PDEs. High in vivo clearance in rats was addressed with the help of metabolite identification (ID) studies. These findings combined resulted in compound 39, a promising potent inhibitor of PDE10A with good in vivo metabolic stability in rats and efficacy in a rodent behavioral model. Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodiesterase 10A (PDE10A) inhibitors.,Hu E, Kunz RK, Rumfelt S, Chen N, Burli R, Li C, Andrews KL, Zhang J, Chmait S, Kogan J, Lindstrom M, Hitchcock SA, Treanor J Bioorg Med Chem Lett. 2012 Mar 15;22(6):2262-5. Epub 2012 Feb 8. PMID:22365755[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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