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| | <StructureSection load='1y2h' size='340' side='right'caption='[[1y2h]], [[Resolution|resolution]] 2.40Å' scene=''> | | <StructureSection load='1y2h' size='340' side='right'caption='[[1y2h]], [[Resolution|resolution]] 2.40Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1y2h]] is a 2 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=1Y2H OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1Y2H FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1y2h]] is a 2 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=1Y2H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1Y2H FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6DE:1-(2-CHLOROPHENYL)-3,5-DIMETHYL-1H-PYRAZOLE-4-CARBOXYLIC+ACID+ETHYL+ESTER'>6DE</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]] 2.4Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=6DE:1-(2-CHLOROPHENYL)-3,5-DIMETHYL-1H-PYRAZOLE-4-CARBOXYLIC+ACID+ETHYL+ESTER'>6DE</scene>, <scene name='pdbligand=CME:S,S-(2-HYDROXYETHYL)THIOCYSTEINE'>CME</scene>, <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"><div style='overflow: auto; max-height: 3em;'>[[1y2b|1y2b]], [[1y2c|1y2c]], [[1y2d|1y2d]], [[1y2e|1y2e]], [[1y2j|1y2j]], [[1y2k|1y2k]]</div></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=1y2h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1y2h OCA], [https://pdbe.org/1y2h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1y2h RCSB], [https://www.ebi.ac.uk/pdbsum/1y2h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1y2h ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">PDE4B ([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://proteopedia.org/fgij/fg.htm?mol=1y2h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1y2h OCA], [http://pdbe.org/1y2h PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1y2h RCSB], [http://www.ebi.ac.uk/pdbsum/1y2h PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1y2h 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> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | <jmolCheckbox> | | <jmolCheckbox> |
| | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/y2/1y2h_consurf.spt"</scriptWhenChecked> | | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/y2/1y2h_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: 3',5'-cyclic-nucleotide phosphodiesterase]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
| + | |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Artis, D R]] | + | [[Category: Artis DR]] |
| - | [[Category: Blasdel, L]] | + | [[Category: Blasdel L]] |
| - | [[Category: Bollag, G]] | + | [[Category: Bollag G]] |
| - | [[Category: Card, G L]] | + | [[Category: Card GL]] |
| - | [[Category: England, B P]] | + | [[Category: England BP]] |
| - | [[Category: Fong, D]] | + | [[Category: Fong D]] |
| - | [[Category: Gillette, S]] | + | [[Category: Gillette S]] |
| - | [[Category: Ibrahim, P N]] | + | [[Category: Ibrahim PN]] |
| - | [[Category: Kim, S H]] | + | [[Category: Kim S-H]] |
| - | [[Category: Milburn, M V]] | + | [[Category: Milburn MV]] |
| - | [[Category: Schlessinger, J]] | + | [[Category: Schlessinger J]] |
| - | [[Category: Suzuki, Y]] | + | [[Category: Suzuki Y]] |
| - | [[Category: Zhang, C]] | + | [[Category: Zhang C]] |
| - | [[Category: Zhang, K Y.J]] | + | [[Category: Zhang KYJ]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Pde]]
| + | |
| - | [[Category: Pde4b]]
| + | |
| - | [[Category: Phosphodiesterase]]
| + | |
| - | [[Category: Pyrazole]]
| + | |
| Structural highlights
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]
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 PubMed
Cyclic nucleotide phosphodiesterases (PDEs) comprise a large family of enzymes that regulate a variety of cellular processes. We describe a family of potent PDE4 inhibitors discovered using an efficient method for scaffold-based drug design. This method involves an iterative approach starting with low-affinity screening of compounds followed by high-throughput cocrystallography to reveal the molecular basis underlying the activity of the newly identified compounds. Through detailed structural analysis of the interaction of the initially discovered pyrazole carboxylic ester scaffold with PDE4D using X-ray crystallography, we identified three sites of chemical substitution and designed small selective libraries of scaffold derivatives with modifications at these sites. A 4,000-fold increase in the potency of this PDE4 inhibitor was achieved after only two rounds of chemical synthesis and the structural analysis of seven pyrazole derivatives bound to PDE4B or PDE4D, revealing the robustness of this approach for identifying new inhibitors that can be further developed into drug candidates.
A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design.,Card GL, Blasdel L, England BP, Zhang C, Suzuki Y, Gillette S, Fong D, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY Nat Biotechnol. 2005 Feb;23(2):201-7. Epub 2005 Jan 30. PMID:15685167[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
- ↑ Card GL, Blasdel L, England BP, Zhang C, Suzuki Y, Gillette S, Fong D, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY. A family of phosphodiesterase inhibitors discovered by cocrystallography and scaffold-based drug design. Nat Biotechnol. 2005 Feb;23(2):201-7. Epub 2005 Jan 30. PMID:15685167 doi:http://dx.doi.org/10.1038/nbt1059
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