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| | ==Catalytic domain of human phosphodiesterase 4b2b in complex with a 5-heterocycle pyrazolopyridine inhibitor== | | ==Catalytic domain of human phosphodiesterase 4b2b in complex with a 5-heterocycle pyrazolopyridine inhibitor== |
| - | <StructureSection load='3o57' size='340' side='right' caption='[[3o57]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='3o57' size='340' side='right'caption='[[3o57]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3o57]] is a 1 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=3O57 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3O57 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3o57]] 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=3O57 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3O57 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ARS:ARSENIC'>ARS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZG2:5-[5-BENZYL-4-(2-OXO-2-PYRROLIDIN-1-YLETHYL)-1,3-OXAZOL-2-YL]-1-ETHYL-N-(TETRAHYDRO-2H-PYRAN-4-YL)-1H-PYRAZOLO[3,4-B]PYRIDIN-4-AMINE'>ZG2</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]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3d3p|3d3p]], [[3o56|3o56]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ARS:ARSENIC'>ARS</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=ZG2:5-[5-BENZYL-4-(2-OXO-2-PYRROLIDIN-1-YLETHYL)-1,3-OXAZOL-2-YL]-1-ETHYL-N-(TETRAHYDRO-2H-PYRAN-4-YL)-1H-PYRAZOLO[3,4-B]PYRIDIN-4-AMINE'>ZG2</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE4B, DPDE4 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=3o57 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o57 OCA], [https://pdbe.org/3o57 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3o57 RCSB], [https://www.ebi.ac.uk/pdbsum/3o57 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3o57 ProSAT]</span></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=3o57 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3o57 OCA], [http://pdbe.org/3o57 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3o57 RCSB], [http://www.ebi.ac.uk/pdbsum/3o57 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3o57 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://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> | + | [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> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Phosphodiesterase|Phosphodiesterase]] | + | *[[Phosphodiesterase 3D structures|Phosphodiesterase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 3',5'-cyclic-nucleotide phosphodiesterase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Neu, M]] | + | [[Category: Neu M]] |
| - | [[Category: Somers, D O]] | + | [[Category: Somers DO]] |
| - | [[Category: Camp binding]]
| + | |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Pde]]
| + | |
| - | [[Category: Phosphodiesterase]]
| + | |
| Structural highlights
3o57 is a 1 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 2Å |
| Ligands: | , , , , |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
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.[1] [2]
Publication Abstract from PubMed
Following the discovery of 4-(substituted amino)-1-alkyl-pyrazolo[3,4-b]pyridine-5-carboxamides as potent and selective phosphodiesterase 4B inhibitors, [Hamblin, J. N.; Angell, T.; Ballentine, S., et al. Bioorg. Med. Chem. Lett.2008, 18, 4237] the SAR of the 5-position was investigated further. A range of substituted heterocycles showed good potencies against PDE4. Optimisation using X-ray crystallography and computational modelling led to the discovery of 16, with sub-nM inhibition of LPS-induced TNF-alpha production from isolated human peripheral blood mononuclear cells.
Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR.,Mitchell CJ, Ballantine SP, Coe DM, Cook CM, Delves CJ, Dowle MD, Edlin CD, Hamblin JN, Holman S, Johnson MR, Jones PS, Keeling SE, Kranz M, Lindvall M, Lucas FS, Neu M, Solanke YE, Somers DO, Trivedi NA, Wiseman JO Bioorg Med Chem Lett. 2010 Oct 1;20(19):5803-6. Epub 2010 Aug 5. PMID:20732811[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Xu RX, Hassell AM, Vanderwall D, Lambert MH, Holmes WD, Luther MA, Rocque WJ, Milburn MV, Zhao Y, Ke H, Nolte RT. Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. Science. 2000 Jun 9;288(5472):1822-5. PMID:10846163
- ↑ Xu RX, Rocque WJ, Lambert MH, Vanderwall DE, Luther MA, Nolte RT. Crystal structures of the catalytic domain of phosphodiesterase 4B complexed with AMP, 8-Br-AMP, and rolipram. J Mol Biol. 2004 Mar 19;337(2):355-65. PMID:15003452 doi:http://dx.doi.org/10.1016/j.jmb.2004.01.040
- ↑ Mitchell CJ, Ballantine SP, Coe DM, Cook CM, Delves CJ, Dowle MD, Edlin CD, Hamblin JN, Holman S, Johnson MR, Jones PS, Keeling SE, Kranz M, Lindvall M, Lucas FS, Neu M, Solanke YE, Somers DO, Trivedi NA, Wiseman JO. Pyrazolopyridines as potent PDE4B inhibitors: 5-heterocycle SAR. Bioorg Med Chem Lett. 2010 Oct 1;20(19):5803-6. Epub 2010 Aug 5. PMID:20732811 doi:10.1016/j.bmcl.2010.07.136
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