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4xy2

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Revision as of 17:58, 26 April 2023

Crystal structure of PDE10A in complex with ASP9436

Structural highlights

4xy2 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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 PubMed

We synthesized several biaryl derivatives as PDE10A inhibitors to prevent phototoxicity of 2-[4-({[1-methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl]oxy}methyl)phenyl]quinoline (1) and found that the energy difference between the energy-minimized conformation and the coplanar conformation of the biaryl moiety helped facilitate prediction of the phototoxic potential of biaryl compounds. Replacement of the quinoline ring of 1 with N-methyl benzimidazole increased this energy difference and prevented phototoxicity in the 3T3 NRU test. Further optimization identified 1-methyl-5-(1-methyl-3-{[4-(1-methyl-1H-benzimidazol-4-yl)phenoxy]methyl}-1H-pyra zol-4-yl)pyridin-2(1H)-one (38b). Compound 38b exhibited good selectivity against other PDEs, and oral administration of 38b improved visual-recognition memory deficit in mice at doses of 0.001 and 0.003mg/kg in the novel object recognition test. ASP9436 (sesquiphosphate of 38b) may therefore be used for the treatment of schizophrenia with a low risk of phototoxicity.

Addressing phototoxicity observed in a novel series of biaryl derivatives: Discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436.,Hamaguchi W, Masuda N, Miyamoto S, Kikuchi S, Narazaki F, Shiina Y, Seo R, Amano Y, Mihara T, Moriguchi H, Hattori K Bioorg Med Chem. 2015 Jul 1;23(13):3351-67. doi: 10.1016/j.bmc.2015.04.052. Epub , 2015 Apr 25. PMID:25960322^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Wang H, Liu Y, Hou J, Zheng M, Robinson H, Ke H. Structural insight into substrate specificity of phosphodiesterase 10. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5782-7. Epub 2007 Mar 26. PMID:17389385
↑ Hamaguchi W, Masuda N, Miyamoto S, Kikuchi S, Narazaki F, Shiina Y, Seo R, Amano Y, Mihara T, Moriguchi H, Hattori K. Addressing phototoxicity observed in a novel series of biaryl derivatives: Discovery of potent, selective and orally active phosphodiesterase 10A inhibitor ASP9436. Bioorg Med Chem. 2015 Jul 1;23(13):3351-67. doi: 10.1016/j.bmc.2015.04.052. Epub , 2015 Apr 25. PMID:25960322 doi:http://dx.doi.org/10.1016/j.bmc.2015.04.052

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4xy2"

Categories: Homo sapiens | Large Structures | Amano Y | Honbou K

@@ Line 3: / Line 3: @@
 <StructureSection load='4xy2' size='340' side='right'caption='[[4xy2]], [[Resolution|resolution]] 2.03&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4xy2]] 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=4XY2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4XY2 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4xy2]] 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=4XY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4XY2 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=490:1-METHYL-5-(1-METHYL-3-{[4-(1-METHYL-1H-BENZIMIDAZOL-4-YL)PHENOXY]METHYL}-1H-PYRAZOL-4-YL)PYRIDIN-2(1H)-ONE'>490</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" id="ligandDat"><scene name='pdbligand=490:1-METHYL-5-(1-METHYL-3-{[4-(1-METHYL-1H-BENZIMIDAZOL-4-YL)PHENOXY]METHYL}-1H-PYRAZOL-4-YL)PYRIDIN-2(1H)-ONE'>490</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4xy2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xy2 OCA], [https://pdbe.org/4xy2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4xy2 RCSB], [https://www.ebi.ac.uk/pdbsum/4xy2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4xy2 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=4xy2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4xy2 OCA], [http://pdbe.org/4xy2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4xy2 RCSB], [http://www.ebi.ac.uk/pdbsum/4xy2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4xy2 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>
+[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 ==
@@ Line 27: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Amano, Y]]
+[[Category: Amano Y]]
-[[Category: Honbou, K]]
+[[Category: Honbou K]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Phosphodiesterase]]

4xy2

From Proteopedia

Revision as of 17:58, 26 April 2023

Crystal structure of PDE10A in complex with ASP9436

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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