1y2h
From Proteopedia
(New page: 200px<br /> <applet load="1y2h" size="450" color="white" frame="true" align="right" spinBox="true" caption="1y2h, resolution 2.40Å" /> '''Catalytic Domain Of...) |
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| - | [[Image:1y2h.gif|left|200px]]<br /> | + | [[Image:1y2h.gif|left|200px]]<br /><applet load="1y2h" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1y2h, resolution 2.40Å" /> | caption="1y2h, resolution 2.40Å" /> | ||
'''Catalytic Domain Of Human Phosphodiesterase 4B In Complex With 1-(2-chloro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester'''<br /> | '''Catalytic Domain Of Human Phosphodiesterase 4B In Complex With 1-(2-chloro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Cyclic nucleotide phosphodiesterases (PDEs) comprise a large family of | + | 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. |
==About this Structure== | ==About this Structure== | ||
| - | 1Y2H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, MG and 6DE as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http:// | + | 1Y2H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=MG:'>MG</scene> and <scene name='pdbligand=6DE:'>6DE</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Y2H OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Artis, D | + | [[Category: Artis, D R.]] |
[[Category: Blasdel, L.]] | [[Category: Blasdel, L.]] | ||
[[Category: Bollag, G.]] | [[Category: Bollag, G.]] | ||
| - | [[Category: Card, G | + | [[Category: Card, G L.]] |
| - | [[Category: England, B | + | [[Category: England, B P.]] |
[[Category: Fong, D.]] | [[Category: Fong, D.]] | ||
[[Category: Gillette, S.]] | [[Category: Gillette, S.]] | ||
| - | [[Category: Ibrahim, P | + | [[Category: Ibrahim, P N.]] |
| - | [[Category: Kim, S | + | [[Category: Kim, S H.]] |
| - | [[Category: Milburn, M | + | [[Category: Milburn, M V.]] |
[[Category: Schlessinger, J.]] | [[Category: Schlessinger, J.]] | ||
[[Category: Suzuki, Y.]] | [[Category: Suzuki, Y.]] | ||
[[Category: Zhang, C.]] | [[Category: Zhang, C.]] | ||
| - | [[Category: Zhang, K | + | [[Category: Zhang, K Y.J.]] |
[[Category: 6DE]] | [[Category: 6DE]] | ||
[[Category: MG]] | [[Category: MG]] | ||
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[[Category: pyrazole]] | [[Category: pyrazole]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:01:07 2008'' |
Revision as of 14:01, 21 February 2008
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Catalytic Domain Of Human Phosphodiesterase 4B In Complex With 1-(2-chloro-phenyl)-3,5-dimethyl-1H-pyrazole-4-carboxylic acid ethyl ester
Overview
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.
About this Structure
1Y2H is a Single protein structure of sequence from Homo sapiens with , and as ligands. Active as 3',5'-cyclic-nucleotide phosphodiesterase, with EC number 3.1.4.17 Full crystallographic information is available from OCA.
Reference
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
Page seeded by OCA on Thu Feb 21 16:01:07 2008
Categories: 3',5'-cyclic-nucleotide phosphodiesterase | Homo sapiens | Single protein | Artis, D R. | Blasdel, L. | Bollag, G. | Card, G L. | England, B P. | Fong, D. | Gillette, S. | Ibrahim, P N. | Kim, S H. | Milburn, M V. | Schlessinger, J. | Suzuki, Y. | Zhang, C. | Zhang, K Y.J. | 6DE | MG | ZN | Pde | Pde4b | Phosphodiesterase | Pyrazole
