5b4l: Difference between revisions
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==Crystal structure of the catalytic domain of human PDE10A complexed with 1-(cyclopropylmethyl)-5-(2-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)ethoxy)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one== | ==Crystal structure of the catalytic domain of human PDE10A complexed with 1-(cyclopropylmethyl)-5-(2-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)ethoxy)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one== | ||
<StructureSection load='5b4l' size='340' side='right' caption='[[5b4l]], [[Resolution|resolution]] 2.40Å' scene=''> | <StructureSection load='5b4l' size='340' side='right'caption='[[5b4l]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[5b4l]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5B4L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5B4L FirstGlance]. <br> | <table><tr><td colspan='2'>[[5b4l]] is a 2 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=5B4L OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5B4L FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6DW:1-(CYCLOPROPYLMETHYL)-5-(2-(2,3-DIHYDRO-1H-IMIDAZO[1,2-A]BENZIMIDAZOL-1-YL)ETHOXY)-3-(1-PHENYL-1H-PYRAZOL-5-YL)PYRIDAZIN-4(1H)-ONE'>6DW</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=6DW:1-(CYCLOPROPYLMETHYL)-5-(2-(2,3-DIHYDRO-1H-IMIDAZO[1,2-A]BENZIMIDAZOL-1-YL)ETHOXY)-3-(1-PHENYL-1H-PYRAZOL-5-YL)PYRIDAZIN-4(1H)-ONE'>6DW</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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">[[5b4k|5b4k]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5b4k|5b4k]]</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 HUMAN])</td></tr> | |||
<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> | <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> | ||
<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=5b4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5b4l OCA], [http://pdbe.org/5b4l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5b4l RCSB], [http://www.ebi.ac.uk/pdbsum/5b4l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5b4l ProSAT]</span></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=5b4l FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5b4l OCA], [http://pdbe.org/5b4l PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5b4l RCSB], [http://www.ebi.ac.uk/pdbsum/5b4l PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5b4l ProSAT]</span></td></tr> | ||
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</div> | </div> | ||
<div class="pdbe-citations 5b4l" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 5b4l" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]] | [[Category: 3',5'-cyclic-nucleotide phosphodiesterase]] | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | |||
[[Category: Oki, H]] | [[Category: Oki, H]] | ||
[[Category: Zama, Y]] | [[Category: Zama, Y]] | ||
[[Category: Hydrolase-hydrolase inhibitor complex]] | [[Category: Hydrolase-hydrolase inhibitor complex]] | ||
Revision as of 11:46, 11 March 2020
Crystal structure of the catalytic domain of human PDE10A complexed with 1-(cyclopropylmethyl)-5-(2-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)ethoxy)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-oneCrystal structure of the catalytic domain of human PDE10A complexed with 1-(cyclopropylmethyl)-5-(2-(2,3-dihydro-1H-imidazo[1,2-a]benzimidazol-1-yl)ethoxy)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one
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 PubMedUtilizing structure-based drug design techniques, we designed and synthesized phosphodiesterase 10A (PDE10A) inhibitors based on pyridazin-4(1H)-one. These compounds can interact with Tyr683 in the PDE10A selectivity pocket. Pyridazin-4(1H)-one derivative 1 was linked with a benzimidazole group through an alkyl spacer to interact with the OH of Tyr683 and fill the PDE10A selectivity pocket. After optimizing the linker length, we identified 1-(cyclopropylmethyl)-5-[3-(1-methyl-1H-benzimidazol-2-yl)propoxy]-3-(1-phenyl-1H -pyrazol-5-yl)pyridazin-4(1H)-one (16f) as having highly potent PDE10A inhibitory activity (IC50=0.76nM) and perfect selectivity against other PDEs (>13,000-fold, IC50=>10,000nM). The crystal structure of 16f bound to PDE10A revealed that the benzimidazole moiety was located deep within the PDE10A selectivity pocket and interacted with Tyr683. Additionally, a bidentate interaction existed between the 5-alkoxypyridazin-4(1H)-one moiety and the conserved Gln716 present in all PDEs. Design and synthesis of potent and selective pyridazin-4(1H)-one-based PDE10A inhibitors interacting with Tyr683 in the PDE10A selectivity pocket.,Yoshikawa M, Hitaka T, Hasui T, Fushimi M, Kunitomo J, Kokubo H, Oki H, Nakashima K, Taniguchi T Bioorg Med Chem. 2016 May 25. pii: S0968-0896(16)30382-0. doi:, 10.1016/j.bmc.2016.05.049. PMID:27301679[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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