5uwf: Difference between revisions

Latest revision as of 13:36, 4 October 2023

Crystal structure of human PDE10A in complex with inhibitor 16d

Structural highlights

5uwf 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 1.87Å
Ligands:	8Q7, MG, ZN
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

A series of potent thienotriazolopyrimidinone-based PDE1 inhibitors was discovered. X-ray crystal structures of example compounds from this series in complex with the catalytic domain of PDE1B and PDE10A were determined, allowing optimization of PDE1B potency and PDE selectivity. Reduction of hERG affinity led to greater than a 3000-fold selectivity for PDE1B over hERG. 6-(4-Methoxybenzyl)-9-((tetrahydro-2H-pyran-4-yl)methyl)-8,9,10,11-tetrahydropyri do[4',3':4,5]thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one was identified as an orally bioavailable and brain penetrating PDE1B enzyme inhibitor with potent memory-enhancing effects in a rat model of object recognition memory.

Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties.,Dyck B, Branstetter B, Gharbaoui T, Hudson AR, Breitenbucher JG, Gomez L, Botrous I, Marrone T, Barido R, Allerston CK, Cedervall EP, Xu R, Sridhar V, Barker R, Aertgeerts K, Schmelzer K, Neul D, Lee D, Massari ME, Andersen CB, Sebring K, Zhou X, Petroski R, Limberis J, Augustin M, Chun LE, Edwards TE, Peters M, Tabatabaei A J Med Chem. 2017 Apr 13. doi: 10.1021/acs.jmedchem.7b00302. PMID:28406621^[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
↑ Dyck B, Branstetter B, Gharbaoui T, Hudson AR, Breitenbucher JG, Gomez L, Botrous I, Marrone T, Barido R, Allerston CK, Cedervall EP, Xu R, Sridhar V, Barker R, Aertgeerts K, Schmelzer K, Neul D, Lee D, Massari ME, Andersen CB, Sebring K, Zhou X, Petroski R, Limberis J, Augustin M, Chun LE, Edwards TE, Peters M, Tabatabaei A. Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties. J Med Chem. 2017 Apr 13. doi: 10.1021/acs.jmedchem.7b00302. PMID:28406621 doi:https://dx.doi.org/10.1021/acs.jmedchem.7b00302

Proteopedia Page Contributors and Editors (what is this?)

OCA

[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] Dyck B, Branstetter B, Gharbaoui T, Hudson AR, Breitenbucher JG, Gomez L, Botrous I, Marrone T, Barido R, Allerston CK, Cedervall EP, Xu R, Sridhar V, Barker R, Aertgeerts K, Schmelzer K, Neul D, Lee D, Massari ME, Andersen CB, Sebring K, Zhou X, Petroski R, Limberis J, Augustin M, Chun LE, Edwards TE, Peters M, Tabatabaei A. Discovery of Selective Phosphodiesterase 1 Inhibitors with Memory Enhancing Properties. J Med Chem. 2017 Apr 13. doi: 10.1021/acs.jmedchem.7b00302. PMID:28406621 doi:https://dx.doi.org/10.1021/acs.jmedchem.7b00302

[1]

[2]

@@ Line 3: / Line 3: @@
 <StructureSection load='5uwf' size='340' side='right'caption='[[5uwf]], [[Resolution|resolution]] 1.87&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5uwf]] 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=5UWF OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=5UWF FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5uwf]] 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=5UWF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5UWF FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8Q7:9-[(1S)-2,2-DIFLUOROCYCLOPROPANE-1-CARBONYL]-6-[(4-METHOXYPHENYL)METHYL]-8,9,10,11-TETRAHYDROPYRIDO[4,3 4,5]THIENO[3,2-E][1,2,4]TRIAZOLO[1,5-C]PYRIMIDIN-5(6H)-ONE'>8Q7</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]] 1.87&#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=8Q7:9-[(1S)-2,2-DIFLUOROCYCLOPROPANE-1-CARBONYL]-6-[(4-METHOXYPHENYL)METHYL]-8,9,10,11-TETRAHYDROPYRIDO[4,3 4,5]THIENO[3,2-E][1,2,4]TRIAZOLO[1,5-C]PYRIMIDIN-5(6H)-ONE'>8Q7</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://proteopedia.org/fgij/fg.htm?mol=5uwf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uwf OCA], [http://pdbe.org/5uwf PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5uwf RCSB], [http://www.ebi.ac.uk/pdbsum/5uwf PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5uwf 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=5uwf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5uwf OCA], [https://pdbe.org/5uwf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5uwf RCSB], [https://www.ebi.ac.uk/pdbsum/5uwf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5uwf 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 26: / Line 26: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Aertgeerts, K]]
+[[Category: Aertgeerts K]]
-[[Category: Barker, R]]
+[[Category: Barker R]]
-[[Category: Cedervall, E P]]
+[[Category: Cedervall EP]]
-[[Category: Sridhar, V]]
+[[Category: Sridhar V]]
-[[Category: Xu, R]]
+[[Category: Xu R]]
-[[Category: Hydrolase-hydrolase inhibitor complex]]
-[[Category: Phosphodiesterase]]

5uwf: Difference between revisions

Latest revision as of 13:36, 4 October 2023

Crystal structure of human PDE10A in complex with inhibitor 16d

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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