4htz: Difference between revisions

Revision as of 08:14, 9 November 2022

Crystal structure of PDE2 catalytic domain in space group P1

Structural highlights

4htz is a 4 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:	MG, ZN
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PDE2A_HUMAN Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.^[1] ^[2]

Publication Abstract from PubMed

To better understand the structural origins of inhibitor selectivity of human phosphodieasterase families (PDEs 1-11), here we report the X-ray crystal structure of PDE2 in complex with a highly selective, nanomolar inhibitor (BAY60-7550) at 1.9 A resolution, and the structure of apo PDE2 at 2.0 A resolution. The crystal structures reveal that the inhibitor binds to the PDE2 active site by using not only the conserved glutamine-switch mechanism for substrate binding, but also a binding-induced, hydrophobic pocket that was not reported previously. In silico affinity profiling by molecular docking indicates that the inhibitor binding to this pocket contributes significantly to the binding affinity and thereby improves the inhibitor selectivity for PDE2. Our results highlight a structure-based design strategy that exploits the potential binding-induced pockets to achieve higher selectivity in the PDE inhibitor development.

X-ray Crystal Structure of Phosphodiesterase 2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals a Binding-Induced Pocket Important for Selectivity.,Zhu J, Yang Q, Dai D, Huang Q J Am Chem Soc. 2013 Aug 14;135(32):11708-11. doi: 10.1021/ja404449g. Epub 2013, Aug 2. PMID:23899287^[3]

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

References

↑ Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T. Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system. Biochemistry. 2005 Jun 14;44(23):8312-25. PMID:15938621 doi:10.1021/bi047313h
↑ Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci U S A. 2009 Oct 14. PMID:19828435
↑ Zhu J, Yang Q, Dai D, Huang Q. X-ray Crystal Structure of Phosphodiesterase 2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals a Binding-Induced Pocket Important for Selectivity. J Am Chem Soc. 2013 Aug 14;135(32):11708-11. doi: 10.1021/ja404449g. Epub 2013, Aug 2. PMID:23899287 doi:10.1021/ja404449g

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Iffland A, Kohls D, Low S, Luan J, Zhang Y, Kothe M, Cao Q, Kamath AV, Ding YH, Ellenberger T. Structural determinants for inhibitor specificity and selectivity in PDE2A using the wheat germ in vitro translation system. Biochemistry. 2005 Jun 14;44(23):8312-25. PMID:15938621 doi:10.1021/bi047313h

[2] Pandit J, Forman MD, Fennell KF, Dillman KS, Menniti FS. Mechanism for the allosteric regulation of phosphodiesterase 2A deduced from the X-ray structure of a near full-length construct. Proc Natl Acad Sci U S A. 2009 Oct 14. PMID:19828435

[3] Zhu J, Yang Q, Dai D, Huang Q. X-ray Crystal Structure of Phosphodiesterase 2 in Complex with a Highly Selective, Nanomolar Inhibitor Reveals a Binding-Induced Pocket Important for Selectivity. J Am Chem Soc. 2013 Aug 14;135(32):11708-11. doi: 10.1021/ja404449g. Epub 2013, Aug 2. PMID:23899287 doi:10.1021/ja404449g

[1]

[2]

[3]

@@ Line 1: / Line 1: @@
 ==Crystal structure of PDE2 catalytic domain in space group P1==
-<StructureSection load='4htz' size='340' side='right' caption='[[4htz]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
+<StructureSection load='4htz' size='340' side='right'caption='[[4htz]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4htz]] is a 4 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=4HTZ OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HTZ FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4htz]] is a 4 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=4HTZ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HTZ FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4htx|4htx]]</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=4htz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4htz OCA], [https://pdbe.org/4htz PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4htz RCSB], [https://www.ebi.ac.uk/pdbsum/4htz PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4htz ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE2A ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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-nucleotide_phosphodiesterase 3',5'-cyclic-nucleotide phosphodiesterase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.1.4.17 3.1.4.17] </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=4htz FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4htz OCA], [http://pdbe.org/4htz PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4htz RCSB], [http://www.ebi.ac.uk/pdbsum/4htz PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4htz ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/PDE2A_HUMAN PDE2A_HUMAN]] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.<ref>PMID:15938621</ref> <ref>PMID:19828435</ref>
+[https://www.uniprot.org/uniprot/PDE2A_HUMAN PDE2A_HUMAN] Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.<ref>PMID:15938621</ref> <ref>PMID:19828435</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 21: / Line 18: @@
 </div>
 <div class="pdbe-citations 4htz" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
+[[Category: Large Structures]]
-[[Category: Huang, Q]]
+[[Category: Huang Q]]
-[[Category: Zhu, J]]
+[[Category: Zhu J]]
-[[Category: Hydrolase]]

4htz: Difference between revisions

Revision as of 08:14, 9 November 2022

Crystal structure of PDE2 catalytic domain in space group P1

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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