6k9u: Difference between revisions

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<StructureSection load='6k9u' size='340' side='right'caption='[[6k9u]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
<StructureSection load='6k9u' size='340' side='right'caption='[[6k9u]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6k9u]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6K9U OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6K9U FirstGlance]. <br>
<table><tr><td colspan='2'>[[6k9u]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6K9U OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6K9U FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=D4L:2-(3,7-dimethylquinoxalin-2-yl)-~{N}-(oxan-4-yl)-5-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidin-7-amine'>D4L</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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]] 2.35&#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=10116 Buffalo rat])</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=D4L:2-(3,7-dimethylquinoxalin-2-yl)-~{N}-(oxan-4-yl)-5-pyrrolidin-1-yl-pyrazolo[1,5-a]pyrimidin-7-amine'>D4L</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=6k9u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6k9u OCA], [http://pdbe.org/6k9u PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6k9u RCSB], [http://www.ebi.ac.uk/pdbsum/6k9u PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6k9u 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=6k9u FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6k9u OCA], [https://pdbe.org/6k9u PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6k9u RCSB], [https://www.ebi.ac.uk/pdbsum/6k9u PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6k9u ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/PDE10_RAT PDE10_RAT]] 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:10583409</ref>
[https://www.uniprot.org/uniprot/PDE10_RAT PDE10_RAT] 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:10583409</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
We have developed a new class of PDE10A inhibitor, a pyrazolo[1,5-a]pyrimidine derivative MT-3014 (1). A previous compound introduced was deprioritized due to concerns for E/Z-isomerization and glutathione-adduct formation at the core stilbene structure. We discovered pyrazolo [1,5-a] pyrimidine as a new lead scaffold by structure-based drug design utilizing a co-crystal structure with PDE10A. The lead compound was optimized for in vitro activity, solubility, and selectivity against human ether-a-go-go related gene cardiac channel binding. We observed that MT-3014 shows excellent efficacy in rat conditioned avoidance response test and suitable pharmacokinetic properties in rats, especially high brain penetration.


Discovery of a pyrazolo[1,5-a]pyrimidine derivative (MT-3014) as a highly selective PDE10A inhibitor via core structure transformation from the stilbene moiety.,Koizumi Y, Tanaka Y, Matsumura T, Kadoh Y, Miyoshi H, Hongu M, Takedomi K, Kotera J, Sasaki T, Taniguchi H, Watanabe Y, Takakuwa M, Kojima K, Baba N, Nakamura I, Kawanishi E Bioorg Med Chem. 2019 Jun 19. pii: S0968-0896(19)30495-X. doi:, 10.1016/j.bmc.2019.06.021. PMID:31235264<ref>PMID:31235264</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 6k9u" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Buffalo rat]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Koizumi, Y]]
[[Category: Rattus norvegicus]]
[[Category: Takedomi, K]]
[[Category: Koizumi Y]]
[[Category: Bbb]]
[[Category: Takedomi K]]
[[Category: Brain penetration]]
[[Category: Crystatl structure]]
[[Category: Enzyme]]
[[Category: Hydrolase]]
[[Category: Inhibitor]]
[[Category: Pde]]
[[Category: Schizophrenia]]

Latest revision as of 10:41, 27 March 2024

Discovery of Pyrazolo[1,5-a]pyrimidine Derivative as a Highly Selective PDE10A Inhibitor

6k9u, resolution 2.35Å

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