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==Crystal structure of PDE4B catalytic domain in complex with a pyrazolopyridine inhibitor== | ==Crystal structure of PDE4B catalytic domain in complex with a pyrazolopyridine inhibitor== | ||
<StructureSection load='3d3p' size='340' side='right' caption='[[3d3p]], [[Resolution|resolution]] 1.75Å' scene=''> | <StructureSection load='3d3p' size='340' side='right'caption='[[3d3p]], [[Resolution|resolution]] 1.75Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[3d3p]] is a 1 chain structure with sequence from [ | <table><tr><td colspan='2'>[[3d3p]] is a 1 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=3D3P OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3D3P FirstGlance]. <br> | ||
</td></tr><tr><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=20A:1-ETHYL-N-(PHENYLMETHYL)-4-(TETRAHYDRO-2H-PYRAN-4-YLAMINO)-1H-PYRAZOLO[3,4-B]PYRIDINE-5-CARBOXAMIDE'>20A</scene>, <scene name='pdbligand=ARS:ARSENIC'>ARS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.75Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=20A:1-ETHYL-N-(PHENYLMETHYL)-4-(TETRAHYDRO-2H-PYRAN-4-YLAMINO)-1H-PYRAZOLO[3,4-B]PYRIDINE-5-CARBOXAMIDE'>20A</scene>, <scene name='pdbligand=ARS:ARSENIC'>ARS</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |||
<tr | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3d3p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3d3p OCA], [https://pdbe.org/3d3p PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3d3p RCSB], [https://www.ebi.ac.uk/pdbsum/3d3p PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3d3p ProSAT]</span></td></tr> | ||
</table> | |||
<table> | == Function == | ||
[https://www.uniprot.org/uniprot/PDE4B_HUMAN PDE4B_HUMAN] Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.<ref>PMID:10846163</ref> <ref>PMID:15003452</ref> | |||
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
Check<jmol> | Check<jmol> | ||
<jmolCheckbox> | <jmolCheckbox> | ||
<scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d3/3d3p_consurf.spt"</scriptWhenChecked> | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d3/3d3p_consurf.spt"</scriptWhenChecked> | ||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
<text>to colour the structure by Evolutionary Conservation</text> | <text>to colour the structure by Evolutionary Conservation</text> | ||
</jmolCheckbox> | </jmolCheckbox> | ||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/ | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=3d3p ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
| Line 26: | Line 28: | ||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 3d3p" style="background-color:#fffaf0;"></div> | |||
==See Also== | ==See Also== | ||
*[[Phosphodiesterase|Phosphodiesterase]] | *[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: Neu M]] | ||
[[Category: | [[Category: Somers DO]] | ||
Latest revision as of 15:40, 30 August 2023
Crystal structure of PDE4B catalytic domain in complex with a pyrazolopyridine inhibitorCrystal structure of PDE4B catalytic domain in complex with a pyrazolopyridine inhibitor
Structural highlights
FunctionPDE4B_HUMAN Hydrolyzes the second messenger cAMP, which is a key regulator of many important physiological processes. May be involved in mediating central nervous system effects of therapeutic agents ranging from antidepressants to antiasthmatic and anti-inflammatory agents.[1] [2] Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedOptimisation of a high-throughput screening hit resulted in the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective inhibitors of Phosphodiesterase 4 (PDE4). Herein, we describe early SAR studies around this novel template highlighting preferred substituents and rationalization of SAR through X-ray crystal structures of analogues bound to the PDE4 active site. Pyrazolopyridine 20a was found to be a potent and selective PDE4 inhibitor which also inhibits LPS induced TNF-alpha production from isolated human peripheral blood mononuclear cells and has an encouraging rat PK profile suitable for oral dosing. Pyrazolopyridines as a novel structural class of potent and selective PDE4 inhibitors.,Hamblin JN, Angell TD, Ballantine SP, Cook CM, Cooper AW, Dawson J, Delves CJ, Jones PS, Lindvall M, Lucas FS, Mitchell CJ, Neu MY, Ranshaw LE, Solanke YE, Somers DO, Wiseman JO Bioorg Med Chem Lett. 2008 Jul 15;18(14):4237-41. Epub 2008 May 17. PMID:18539455[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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