6ijh

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of PDE10 in complex with inhibitor AF-399/14387019

Structural highlights

6ijh 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 2.6Å
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

Pulmonary arterial hypertension (PAH) causes pathological increase in pulmonary vascular resistance, leading to right-heart failure and eventual death. Previously, phosphodiesterase-10 (PDE10) was reported to be a promising target for PAH based on the studies with a nonselective PDE inhibitor papaverine, but little progress has been made to confirm the practical application of PDE10 inhibitors. To validate whether PAH is ameliorated by PDE10 inhibition rather than other PDE isoforms, here we report an integrated strategy to discover highly selective PDE10 inhibitors as chemical probes. Structural optimization resulted in a PDE10 inhibitor 2b with subnanomolar affinity and good selectivity of >45000-fold against other PDEs. The cocrystal structure of the PDE10-2b complex revealed an important H-bond interaction between 2b and Tyr693. Finally, compound 2b significantly decreased the arterial pressure in PAH rats and thus validated the potential of PDE10 as a novel anti-PAH target. These findings suggest that PDE10 inhibition may be a viable treatment option for PAH.

Validation of Phosphodiesterase-10 as a Novel Target for Pulmonary Arterial Hypertension via Highly Selective and Subnanomolar Inhibitors.,Huang YY, Yu YF, Zhang C, Chen Y, Zhou Q, Li Z, Zhou S, Li Z, Guo L, Wu D, Wu Y, Luo HB J Med Chem. 2019 Mar 29. doi: 10.1021/acs.jmedchem.9b00224. PMID:30888810^[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
↑ Huang YY, Yu YF, Zhang C, Chen Y, Zhou Q, Li Z, Zhou S, Li Z, Guo L, Wu D, Wu Y, Luo HB. Validation of Phosphodiesterase-10 as a Novel Target for Pulmonary Arterial Hypertension via Highly Selective and Subnanomolar Inhibitors. J Med Chem. 2019 Mar 29. doi: 10.1021/acs.jmedchem.9b00224. PMID:30888810 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b00224

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/6ijh"

@@ Line 3: / Line 3: @@
 <StructureSection load='6ijh' size='340' side='right'caption='[[6ijh]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6ijh]] 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=6IJH OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6IJH FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6ijh]] 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=6IJH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6IJH FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=AEO:2-[2-(4-phenyl-5-sulfanylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]-1H-benzo[de]isoquinoline-1,3(2H)-dione'>AEO</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]] 2.6&#8491;</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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=AEO:2-[2-(4-phenyl-5-sulfanylidene-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]-1H-benzo[de]isoquinoline-1,3(2H)-dione'>AEO</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6ijh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ijh OCA], [http://pdbe.org/6ijh PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6ijh RCSB], [http://www.ebi.ac.uk/pdbsum/6ijh PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6ijh 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=6ijh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ijh OCA], [https://pdbe.org/6ijh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ijh RCSB], [https://www.ebi.ac.uk/pdbsum/6ijh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ijh 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 19: / Line 19: @@
 </div>
 <div class="pdbe-citations 6ijh" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Huang, Y Y]]
+[[Category: Huang YY]]
-[[Category: Luo, H B]]
+[[Category: Luo HB]]
-[[Category: Wu, D]]
+[[Category: Wu D]]
-[[Category: Wu, Y]]
+[[Category: Wu Y]]
-[[Category: Yu, Y F]]
+[[Category: Yu YF]]
-[[Category: Zhang, C]]
+[[Category: Zhang C]]
-[[Category: Hydrolase-inhibitor complex]]

6ijh

From Proteopedia

Current revision

Crystal structure of PDE10 in complex with inhibitor AF-399/14387019

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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