5xkm

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==Crystal structure of human phosphodiesterase 2A in complex with 6-methyl-N-(1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide==
==Crystal structure of human phosphodiesterase 2A in complex with 6-methyl-N-(1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide==
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<StructureSection load='5xkm' size='340' side='right' caption='[[5xkm]], [[Resolution|resolution]] 2.16&Aring;' scene=''>
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<StructureSection load='5xkm' size='340' side='right'caption='[[5xkm]], [[Resolution|resolution]] 2.16&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[5xkm]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5XKM OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5XKM FirstGlance]. <br>
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<table><tr><td colspan='2'>[[5xkm]] is a 6 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=5XKM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5XKM 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=87R:6-methyl-N-[(1R)-1-[4-(trifluoromethyloxy)phenyl]propyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide'>87R</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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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]] 2.16&#8491;</td></tr>
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<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=87R:6-methyl-N-[(1R)-1-[4-(trifluoromethyloxy)phenyl]propyl]pyrazolo[1,5-a]pyrimidine-3-carboxamide'>87R</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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/3',5'-cyclic-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] </span></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=5xkm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xkm OCA], [https://pdbe.org/5xkm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5xkm RCSB], [https://www.ebi.ac.uk/pdbsum/5xkm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5xkm ProSAT]</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=5xkm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5xkm OCA], [http://pdbe.org/5xkm PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5xkm RCSB], [http://www.ebi.ac.uk/pdbsum/5xkm PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5xkm ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/PDE2A_HUMAN PDE2A_HUMAN]] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.<ref>PMID:15938621</ref> <ref>PMID:19828435</ref>
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[https://www.uniprot.org/uniprot/PDE2A_HUMAN PDE2A_HUMAN] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.<ref>PMID:15938621</ref> <ref>PMID:19828435</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Herein, we describe the discovery of a potent, selective, brain-penetrating, in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To identify high-quality leads suitable for optimization and enable validation of the physiological function of PDE2A in vivo, structural modifications of the high-throughput screening hit 18 were performed. Our lead generation efforts revealed three key potency-enhancing functionalities with minimal increases in molecular weight (MW) and no change in topological polar surface area (TPSA). Combining these structural elements led to the identification of 6-methyl-N-((1R)-1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5-a]pyrimidine-3 -carboxamide (38a), a molecule with the desired balance of preclinical properties. Further characterization by co-crystal structure analysis of 38a bound to PDE2A uncovered a unique binding mode and provided insights into its observed potency and PDE selectivity. Compound 38a significantly elevated 3',5'-cyclic guanosine monophosphate (cGMP) levels in mouse brain following oral administration, thus validating this compound as a useful pharmacological tool and an attractive lead for future optimization.
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Discovery of an Orally Bioavailable, Brain-Penetrating, In Vivo Active Phosphodiesterase 2A Inhibitor Lead Series for the Treatment of Cognitive Disorders.,Mikami S, Sasaki S, Asano Y, Ujikawa O, Fukumoto S, Nakashima K, Oki H, Kamiguchi N, Imada H, Iwashita H, Taniguchi T J Med Chem. 2017 Jul 31. doi: 10.1021/acs.jmedchem.7b00709. PMID:28759228<ref>PMID:28759228</ref>
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==See Also==
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*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 5xkm" style="background-color:#fffaf0;"></div>
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== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]]
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[[Category: Homo sapiens]]
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[[Category: Human]]
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[[Category: Large Structures]]
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[[Category: Kondo, M]]
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[[Category: Kondo M]]
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[[Category: Lane, W]]
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[[Category: Lane W]]
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[[Category: Oki, H]]
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[[Category: Oki H]]
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[[Category: Snell, G]]
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[[Category: Snell G]]
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[[Category: Hydrolase]]
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[[Category: Hydrolase inhibitor]]
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[[Category: Pde2a]]
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Current revision

Crystal structure of human phosphodiesterase 2A in complex with 6-methyl-N-(1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

PDB ID 5xkm

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