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==PDE10a Crystal Structure Complexed with Novel Inhibitor==
==PDE10a Crystal Structure Complexed with Novel Inhibitor==
<StructureSection load='4ddl' size='340' side='right' caption='[[4ddl]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
<StructureSection load='4ddl' size='340' side='right'caption='[[4ddl]], [[Resolution|resolution]] 2.07&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4ddl]] 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=4DDL OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DDL FirstGlance]. <br>
<table><tr><td colspan='2'>[[4ddl]] 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=4DDL OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4DDL FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0JQ:2-{1-[5-(6,7-DIMETHOXYCINNOLIN-4-YL)-3-METHYLPYRIDIN-2-YL]PIPERIDIN-4-YL}PROPAN-2-OL'>0JQ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.07&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2oup|2oup]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0JQ:2-{1-[5-(6,7-DIMETHOXYCINNOLIN-4-YL)-3-METHYLPYRIDIN-2-YL]PIPERIDIN-4-YL}PROPAN-2-OL'>0JQ</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=4ddl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ddl OCA], [https://pdbe.org/4ddl PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4ddl RCSB], [https://www.ebi.ac.uk/pdbsum/4ddl PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4ddl 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=4ddl FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4ddl OCA], [http://pdbe.org/4ddl PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4ddl RCSB], [http://www.ebi.ac.uk/pdbsum/4ddl PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4ddl ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== 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;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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==See Also==
==See Also==
*[[Phosphodiesterase|Phosphodiesterase]]
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Homo sapiens]]
[[Category: Chmait, S]]
[[Category: Large Structures]]
[[Category: Jordan, S]]
[[Category: Chmait S]]
[[Category: Zhang, J]]
[[Category: Jordan S]]
[[Category: Hydrolase]]
[[Category: Zhang J]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Phosphodiesterase 10a]]

Latest revision as of 05:46, 21 November 2024

PDE10a Crystal Structure Complexed with Novel InhibitorPDE10a Crystal Structure Complexed with Novel Inhibitor

Structural highlights

4ddl 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.
Method:X-ray diffraction, Resolution 2.07Å
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 report the discovery of 6,7-dimethoxy-4-(pyridin-3-yl)cinnolines as novel inhibitors of phosphodiesterase 10A (PDE10A). Systematic examination and analyses of structure-activity-relationships resulted in single digit nM potency against PDE10A. X-ray co-crystal structure revealed the mode of binding in the enzyme's catalytic domain and the source of selectivity against other PDEs. High in vivo clearance in rats was addressed with the help of metabolite identification (ID) studies. These findings combined resulted in compound 39, a promising potent inhibitor of PDE10A with good in vivo metabolic stability in rats and efficacy in a rodent behavioral model.

Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodiesterase 10A (PDE10A) inhibitors.,Hu E, Kunz RK, Rumfelt S, Chen N, Burli R, Li C, Andrews KL, Zhang J, Chmait S, Kogan J, Lindstrom M, Hitchcock SA, Treanor J Bioorg Med Chem Lett. 2012 Mar 15;22(6):2262-5. Epub 2012 Feb 8. PMID:22365755[2]

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

See Also

References

  1. ↑ 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
  2. ↑ Hu E, Kunz RK, Rumfelt S, Chen N, Burli R, Li C, Andrews KL, Zhang J, Chmait S, Kogan J, Lindstrom M, Hitchcock SA, Treanor J. Discovery of potent, selective, and metabolically stable 4-(pyridin-3-yl)cinnolines as novel phosphodiesterase 10A (PDE10A) inhibitors. Bioorg Med Chem Lett. 2012 Mar 15;22(6):2262-5. Epub 2012 Feb 8. PMID:22365755 doi:10.1016/j.bmcl.2012.01.086

4ddl, resolution 2.07Å

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