4y8c: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older edit
No edit summary
No edit summary
 
(3 intermediate revisions by the same user not shown)
Line 1: Line 1:
==Crystal structure of phosphodiesterase 9 in complex with (S)-C33==
==Crystal structure of phosphodiesterase 9 in complex with (S)-C33==
<StructureSection load='4y8c' size='340' side='right' caption='[[4y8c]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
<StructureSection load='4y8c' size='340' side='right'caption='[[4y8c]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4y8c]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4Y8C OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4Y8C FirstGlance]. <br>
<table><tr><td colspan='2'>[[4y8c]] 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=4Y8C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4Y8C FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=49D:6-{[(1S)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49D</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]] 2.7&#8491;</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-GMP_phosphodiesterase 3',5'-cyclic-GMP phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.35 3.1.4.35] </span></td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=49D:6-{[(1S)-1-(4-CHLOROPHENYL)ETHYL]AMINO}-1-CYCLOPENTYL-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-4-ONE'>49D</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=4y8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y8c OCA], [http://pdbe.org/4y8c PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4y8c RCSB], [http://www.ebi.ac.uk/pdbsum/4y8c PDBsum]</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=4y8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4y8c OCA], [https://pdbe.org/4y8c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4y8c RCSB], [https://www.ebi.ac.uk/pdbsum/4y8c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4y8c ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/PDE9A_HUMAN PDE9A_HUMAN]] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.<ref>PMID:18757755</ref> 
[https://www.uniprot.org/uniprot/PDE9A_HUMAN PDE9A_HUMAN] Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.<ref>PMID:18757755</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Phosphodiesterase-9 (PDE9) inhibitors have been studied as potential therapeutics for treatment of central nervous system diseases and diabetes. Here, we report the discovery of a new category of PDE9 inhibitors by rational design on the basis of the crystal structures. The best compound, (S)-6-((1-(4-chlorophenyl)ethyl)amino)-1-cyclopentyl-1,5,6,7-tetrahydro-4H-pyrazo lo[3,4-day]pyrimidin-4-one [(S)-C33], has an IC50 value of 11 nM against PDE9 and the racemic C33 has bioavailability of 56.5% in the rat pharmacokinetic model. The crystal structures of PDE9 in the complex with racemic C33, (R)-C33, and (S)-C33 reveal subtle conformational asymmetry of two M-loops in the PDE9 dimer and different conformations of two C33 enantiomers. The structures also identified a small hydrophobic pocket that interacts with the tyrosyl tail of (S)-C33 but not with (R)-C33, and is thus possibly useful for improvement of selectivity of PDE9 inhibitors. The asymmetry of the M-loop and the different interactions of the C33 enantiomers imply the necessity to consider the whole PDE9 dimer in the design of inhibitors.
 
Structural Asymmetry of Phosphodiesterase-9A and a Unique Pocket for Selective Binding of a Potent Enantiomeric Inhibitor.,Huang M, Shao Y, Hou J, Cui W, Liang B, Huang Y, Li Z, Wu Y, Zhu X, Liu P, Wan Y, Ke H, Luo HB Mol Pharmacol. 2015 Nov;88(5):836-45. doi: 10.1124/mol.115.099747. Epub 2015 Aug , 27. PMID:26316540<ref>PMID:26316540</ref>


From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
==See Also==
</div>
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
<div class="pdbe-citations 4y8c" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: 3',5'-cyclic-GMP phosphodiesterase]]
[[Category: Homo sapiens]]
[[Category: Huang, M]]
[[Category: Large Structures]]
[[Category: Enantiomeric differentiation]]
[[Category: Huang M]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Inhibitor selectivity pocket]]
[[Category: Pharmacokinetic]]
[[Category: Phosphodiesterase 9a]]

Latest revision as of 16:02, 1 March 2024

Crystal structure of phosphodiesterase 9 in complex with (S)-C33Crystal structure of phosphodiesterase 9 in complex with (S)-C33

Structural highlights

4y8c 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 2.7Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PDE9A_HUMAN Hydrolyzes the second messenger cGMP, which is a key regulator of many important physiological processes.[1]

See Also

References

  1. ↑ Liu S, Mansour MN, Dillman KS, Perez JR, Danley DE, Aeed PA, Simons SP, Lemotte PK, Menniti FS. Structural basis for the catalytic mechanism of human phosphodiesterase 9. Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13309-14. Epub 2008 Aug 29. PMID:18757755

4y8c, resolution 2.70Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=4y8c&oldid=4076725"