1xmu: Difference between revisions
New page: left|200px<br /> <applet load="1xmu" size="450" color="white" frame="true" align="right" spinBox="true" caption="1xmu, resolution 2.30Å" /> '''Catalytic Domain Of... |
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caption="1xmu, resolution 2.30Å" /> | caption="1xmu, resolution 2.30Å" /> | ||
'''Catalytic Domain Of Human Phosphodiesterase 4B In Complex With Roflumilast'''<br /> | '''Catalytic Domain Of Human Phosphodiesterase 4B In Complex With Roflumilast'''<br /> | ||
==Overview== | ==Overview== | ||
Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze | Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases. | ||
==About this Structure== | ==About this Structure== | ||
1XMU is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, MG and ROF 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:// | 1XMU is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences 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=ROF:'>ROF</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=1XMU OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Protein complex]] | [[Category: Protein complex]] | ||
[[Category: Artis, D | [[Category: Artis, D R.]] | ||
[[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: Lee, B.]] | [[Category: Lee, B.]] | ||
[[Category: Luu, C.]] | [[Category: Luu, C.]] | ||
[[Category: Milburn, M | [[Category: Milburn, M V.]] | ||
[[Category: Powell, B.]] | [[Category: Powell, B.]] | ||
[[Category: Schlessinger, J.]] | [[Category: Schlessinger, J.]] | ||
[[Category: Suzuki, Y.]] | [[Category: Suzuki, Y.]] | ||
[[Category: Tabrizizad, M.]] | [[Category: Tabrizizad, M.]] | ||
[[Category: Zhang, K | [[Category: Zhang, K Y.J.]] | ||
[[Category: MG]] | [[Category: MG]] | ||
[[Category: ROF]] | [[Category: ROF]] | ||
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[[Category: roflumilast]] | [[Category: roflumilast]] | ||
''Page seeded by [http:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 15:56:32 2008'' | ||
Revision as of 16:56, 21 February 2008
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Catalytic Domain Of Human Phosphodiesterase 4B In Complex With Roflumilast
OverviewOverview
Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.
About this StructureAbout this Structure
1XMU is a Protein complex structure of sequences 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.
ReferenceReference
Structural basis for the activity of drugs that inhibit phosphodiesterases., Card GL, England BP, Suzuki Y, Fong D, Powell B, Lee B, Luu C, Tabrizizad M, Gillette S, Ibrahim PN, Artis DR, Bollag G, Milburn MV, Kim SH, Schlessinger J, Zhang KY, Structure. 2004 Dec;12(12):2233-47. PMID:15576036
Page seeded by OCA on Thu Feb 21 15:56:32 2008
Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)
OCA- Pages with broken file links
- 3',5'-cyclic-nucleotide phosphodiesterase
- Homo sapiens
- Protein complex
- Artis, D R.
- Bollag, G.
- Card, G L.
- England, B P.
- Fong, D.
- Gillette, S.
- Ibrahim, P N.
- Kim, S H.
- Lee, B.
- Luu, C.
- Milburn, M V.
- Powell, B.
- Schlessinger, J.
- Suzuki, Y.
- Tabrizizad, M.
- Zhang, K Y.J.
- MG
- ROF
- ZN
- Pde
- Pde4b
- Phosphodiesterase
- Roflumilast