5c2e
From Proteopedia
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5c2e]] is a 2 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=5C2E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5C2E FirstGlance]. <br> | <table><tr><td colspan='2'>[[5c2e]] is a 2 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=5C2E OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5C2E FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4PX:3-(1-HYDROXY-2-METHYLPROPAN-2-YL)-5-PHENYL-3,5-DIHYDRO-1H-IMIDAZO[4,5-C][1,8]NAPHTHYRIDINE-2,4-DIONE'>4PX</scene>, <scene name='pdbligand=4Y1:6-CHLORO-N-[(2,4-DIMETHYL-1,3-THIAZOL-5-YL)METHYL]-5-METHYL-2-[2-(PYRIDIN-2-YL)ETHOXY]PYRIMIDIN-4-AMINE'>4Y1</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4PX:3-(1-HYDROXY-2-METHYLPROPAN-2-YL)-5-PHENYL-3,5-DIHYDRO-1H-IMIDAZO[4,5-C][1,8]NAPHTHYRIDINE-2,4-DIONE'>4PX</scene>, <scene name='pdbligand=4Y1:6-CHLORO-N-[(2,4-DIMETHYL-1,3-THIAZOL-5-YL)METHYL]-5-METHYL-2-[2-(PYRIDIN-2-YL)ETHOXY]PYRIMIDIN-4-AMINE'>4Y1</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'>[https://proteopedia.org/fgij/fg.htm?mol=5c2e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c2e OCA], [https://pdbe.org/5c2e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5c2e RCSB], [https://www.ebi.ac.uk/pdbsum/5c2e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5c2e ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=5c2e FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5c2e OCA], [https://pdbe.org/5c2e PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5c2e RCSB], [https://www.ebi.ac.uk/pdbsum/5c2e PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5c2e ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == Function == | ||
[https://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> | [https://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 == | ||
| - | Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing. | ||
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| - | Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis.,Shipe WD, Sharik SS, Barrow JC, McGaughey GB, Theberge CR, Uslaner JM, Yan Y, Renger JJ, Smith SM, Coleman PJ, Cox CD J Med Chem. 2015 Sep 25. PMID:26378882<ref>PMID:26378882</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 5c2e" style="background-color:#fffaf0;"></div> | ||
==See Also== | ==See Also== | ||
Current revision
PDE10 complexed with6-chloro-N-[(2,4-dimethylthiazol-5-yl)methyl]-5-methyl-2-[2-(2-pyridyl)ethoxy]pyrimidin-4-amine
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