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==CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A IN COMPLEX with [1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-N-(naphthalene-2-yl)piperidine-3-carboxamide==
==CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A IN COMPLEX with [1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-N-(naphthalene-2-yl)piperidine-3-carboxamide==
<StructureSection load='5tz3' size='340' side='right' caption='[[5tz3]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
<StructureSection load='5tz3' size='340' side='right'caption='[[5tz3]], [[Resolution|resolution]] 1.72&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5tz3]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5TZ3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5TZ3 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5tz3]] 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=5TZ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5TZ3 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=7OM:(3~{R})-1-(5-METHYL-[1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-YL)-~{N}-NAPHTHALEN-2-YL-PIPERIDINE-3-CARBOXAMIDE'>7OM</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]] 1.72&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5tza|5tza]], [[5tzc|5tzc]], [[5tzh|5tzh]], [[5tzw|5tzw]], [[5tzx|5tzx]], [[5tzz|5tzz]], [[5u00|5u00]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=7OM:(3~{R})-1-(5-METHYL-[1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-YL)-~{N}-NAPHTHALEN-2-YL-PIPERIDINE-3-CARBOXAMIDE'>7OM</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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'>[https://proteopedia.org/fgij/fg.htm?mol=5tz3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tz3 OCA], [https://pdbe.org/5tz3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5tz3 RCSB], [https://www.ebi.ac.uk/pdbsum/5tz3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5tz3 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=5tz3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5tz3 OCA], [http://pdbe.org/5tz3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5tz3 RCSB], [http://www.ebi.ac.uk/pdbsum/5tz3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5tz3 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== 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 ==
A series of potent and selective [1,2,4]triazolo[1,5-a]pyrimidine PDE2a inhibitors is reported. The design and improvement of the binding properties of this series was achieved using X-ray crystal structures in conjunction with careful analysis of electronic and structural requirements for the PDE2a enzyme. One of the lead compounds, compound 27 (DNS-8254), was identified as a potent and highly selective PDE2a enzyme inhibitor with favorable rat pharmacokinetic properties. Interestingly, the increased potency of compound 27 was facilitated by the formation of a halogen bond with the oxygen of Tyr827 present in the PDE2a active site. In vivo, compound 27 demonstrated significant memory enhancing effects in a rat model of novel object recognition. Taken together, these data suggest that compound 27 may be a useful tool to explore the pharmacology of selective PDE2a inhibition.


Design and Synthesis of Novel and Selective Phosphodiesterase 2 (PDE2a) Inhibitors for the Treatment of Memory Disorders.,Gomez L, Massari ME, Vickers T, Freestone G, Vernier W, Ly K, Xu R, McCarrick M, Marrone T, Metz M, Yan YG, Yoder ZW, Lemus R, Broadbent NJ, Barido R, Warren N, Schmelzer K, Neul D, Lee D, Andersen CB, Sebring K, Aertgeerts K, Zhou X, Tabatabaei A, Peters M, Breitenbucher JG J Med Chem. 2017 Feb 21. doi: 10.1021/acs.jmedchem.6b01793. PMID:28165743<ref>PMID:28165743</ref>
==See Also==
 
*[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5tz3" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: 3',5'-cyclic-nucleotide phosphodiesterase]]
[[Category: Homo sapiens]]
[[Category: Aertgeerts, K]]
[[Category: Large Structures]]
[[Category: Xu, R]]
[[Category: Aertgeerts K]]
[[Category: Hydrolase-hydrolase inhibitor complex]]
[[Category: Xu R]]
[[Category: Phosphodiesterase]]

Latest revision as of 17:24, 6 March 2024

CRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A IN COMPLEX with [1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-N-(naphthalene-2-yl)piperidine-3-carboxamideCRYSTAL STRUCTURE OF HUMAN PHOSPHODIESTERASE 2A IN COMPLEX with [1,2,4]triazolo[1,5-a]pyrimidin-7-yl}-N-(naphthalene-2-yl)piperidine-3-carboxamide

Structural highlights

5tz3 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.
Method:X-ray diffraction, Resolution 1.72Å
Ligands:, ,
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]

See Also

References

  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

5tz3, resolution 1.72Å

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