5uwf: Difference between revisions
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==Crystal structure of human PDE10A in complex with inhibitor 16d== | |||
<StructureSection load='5uwf' size='340' side='right' caption='[[5uwf]], [[Resolution|resolution]] 1.87Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5uwf]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5UWF OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5UWF FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8Q7:9-[(1S)-2,2-DIFLUOROCYCLOPROPANE-1-CARBONYL]-6-[(4-METHOXYPHENYL)METHYL]-8,9,10,11-TETRAHYDROPYRIDO[4,3 4,5]THIENO[3,2-E][1,2,4]TRIAZOLO[1,5-C]PYRIMIDIN-5(6H)-ONE'>8Q7</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=5uwf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uwf OCA], [http://pdbe.org/5uwf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uwf RCSB], [http://www.ebi.ac.uk/pdbsum/5uwf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uwf ProSAT]</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 == | |||
A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyri do[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory. | |||
Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.,Dyck B, Branstetter B, Gharbaoui T, Hudson AR, Breitenbucher JG, Gomez L, Botrous I, Marrone T, Barido R, Allerston CK, Cedervall EP, Xu R, Sridhar V, Barker R, Aertgeerts K, Schmelzer K, Neul D, Lee D, Massari ME, Andersen CB, Sebring K, Zhou X, Petroski R, Limberis J, Augustin M, Chun LE, Edwards TE, Peters M, Tabatabaei A J Med Chem. 2017 Apr 13. doi: 10.1021/acs.jmedchem.7b00302. PMID:28406621<ref>PMID:28406621</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5uwf" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Aertgeerts, K]] | |||
[[Category: Barker, R]] | |||
[[Category: Cedervall, E P]] | |||
[[Category: Sridhar, V]] | |||
[[Category: Xu, R]] | |||
[[Category: Hydrolase-hydrolase inhibitor complex]] | |||
[[Category: Phosphodiesterase]] | |||
Revision as of 16:52, 27 April 2017
Crystal structure of human PDE10A in complex with inhibitor 16dCrystal structure of human PDE10A in complex with inhibitor 16d
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 PubMedA series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyri do[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory. Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.,Dyck B, Branstetter B, Gharbaoui T, Hudson AR, Breitenbucher JG, Gomez L, Botrous I, Marrone T, Barido R, Allerston CK, Cedervall EP, Xu R, Sridhar V, Barker R, Aertgeerts K, Schmelzer K, Neul D, Lee D, Massari ME, Andersen CB, Sebring K, Zhou X, Petroski R, Limberis J, Augustin M, Chun LE, Edwards TE, Peters M, Tabatabaei A J Med Chem. 2017 Apr 13. doi: 10.1021/acs.jmedchem.7b00302. PMID:28406621[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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