1gd0
From Proteopedia
(New page: 200px<br /> <applet load="1gd0" size="450" color="white" frame="true" align="right" spinBox="true" caption="1gd0, resolution 1.5Å" /> '''HUMAN MACROPHAGE MIG...) |
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| - | [[Image:1gd0.gif|left|200px]]<br /> | + | [[Image:1gd0.gif|left|200px]]<br /><applet load="1gd0" size="350" color="white" frame="true" align="right" spinBox="true" |
| - | <applet load="1gd0" size=" | + | |
caption="1gd0, resolution 1.5Å" /> | caption="1gd0, resolution 1.5Å" /> | ||
'''HUMAN MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF)'''<br /> | '''HUMAN MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF)'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine | + | Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine released from T-cells and macrophages. Although a detailed understanding of the biological functions of MIF has not yet been clarified, it is known that MIF catalyzes the tautomerization of a nonphysiological molecule, D-dopachrome. Using a structure-based computer-assisted search of two databases of commercially available compounds, we have found 14 novel tautomerase inhibitors of MIF whose K(i) values are in the range of 0.038-7.4 microM. We also have determined the crystal structure of MIF complexed with the hit compound 1. It showed that the hit compound is located in the active site of MIF containing the N-terminal proline which plays an important role in the tautomerase reaction and forms several hydrogen bonds and undergoes hydrophobic interactions. A crystallographic study also revealed that there is a hydrophobic surface which consists of Pro-33, Tyr-36, Trp-108, and Phe-113 at the rim of the active site of MIF, and molecular modeling studies indicated that several more potent hit compounds have the aromatic rings which can interact with this hydrophobic surface. To our knowledge, our compounds are the most potent tautomerase inhibitors of MIF. One of these small, drug-like molecules has been cocrystallized with MIF and binds to the active site for tautomerase activity. Molecular modeling also suggests that the other hit compounds can bind in a similar fashion. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1GD0 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 SO4 and CIT as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1GD0 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=SO4:'>SO4</scene> and <scene name='pdbligand=CIT:'>CIT</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1GD0 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: mif]] | [[Category: mif]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:48:49 2008'' |
Revision as of 10:48, 21 February 2008
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HUMAN MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF)
Contents |
Overview
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine released from T-cells and macrophages. Although a detailed understanding of the biological functions of MIF has not yet been clarified, it is known that MIF catalyzes the tautomerization of a nonphysiological molecule, D-dopachrome. Using a structure-based computer-assisted search of two databases of commercially available compounds, we have found 14 novel tautomerase inhibitors of MIF whose K(i) values are in the range of 0.038-7.4 microM. We also have determined the crystal structure of MIF complexed with the hit compound 1. It showed that the hit compound is located in the active site of MIF containing the N-terminal proline which plays an important role in the tautomerase reaction and forms several hydrogen bonds and undergoes hydrophobic interactions. A crystallographic study also revealed that there is a hydrophobic surface which consists of Pro-33, Tyr-36, Trp-108, and Phe-113 at the rim of the active site of MIF, and molecular modeling studies indicated that several more potent hit compounds have the aromatic rings which can interact with this hydrophobic surface. To our knowledge, our compounds are the most potent tautomerase inhibitors of MIF. One of these small, drug-like molecules has been cocrystallized with MIF and binds to the active site for tautomerase activity. Molecular modeling also suggests that the other hit compounds can bind in a similar fashion.
Disease
Known diseases associated with this structure: Persistent Mullerian duct syndrome, type I OMIM:[600957], Rheumatoid arthritis, systemic juvenile, susceptibility to OMIM:[153620]
About this Structure
1GD0 is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
Coumarin and chromen-4-one analogues as tautomerase inhibitors of macrophage migration inhibitory factor: discovery and X-ray crystallography., Orita M, Yamamoto S, Katayama N, Aoki M, Takayama K, Yamagiwa Y, Seki N, Suzuki H, Kurihara H, Sakashita H, Takeuchi M, Fujita S, Yamada T, Tanaka A, J Med Chem. 2001 Feb 15;44(4):540-7. PMID:11170644
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