1m4a
From Proteopedia
(New page: 200px<br /> <applet load="1m4a" size="450" color="white" frame="true" align="right" spinBox="true" caption="1m4a, resolution 2.18Å" /> '''Crystal Structure o...) |
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| - | [[Image:1m4a.gif|left|200px]]<br /> | + | [[Image:1m4a.gif|left|200px]]<br /><applet load="1m4a" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="1m4a, resolution 2.18Å" /> | caption="1m4a, resolution 2.18Å" /> | ||
'''Crystal Structure of Human Interleukin-2 Y31C Covalently Modified at C31 with (1H-Indol-3-yl)-(2-mercapto-ethoxyimino)-acetic acid'''<br /> | '''Crystal Structure of Human Interleukin-2 Y31C Covalently Modified at C31 with (1H-Indol-3-yl)-(2-mercapto-ethoxyimino)-acetic acid'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Understanding binding properties at protein-protein interfaces has been | + | Understanding binding properties at protein-protein interfaces has been limited to structural and mutational analyses of natural binding partners or small peptides identified by phage display. Here, we present a high-resolution analysis of a nonpeptidyl small molecule, previously discovered by medicinal chemistry [Tilley, J. W., et al. (1997) J. Am. Chem. Soc. 119, 7589-7590], which binds to the cytokine IL-2. The small molecule binds to the same site that binds the IL-2 alpha receptor and buries into a groove not seen in the free structure of IL-2. Comparison of the bound and several free structures shows this site to be composed of two subsites: one is rigid, and the other is highly adaptive. Thermodynamic data suggest the energy barriers between these conformations are low. The subsites were dissected by using a site-directed screening method called tethering, in which small fragments were captured by disulfide interchange with cysteines introduced into IL-2 around these subsites. X-ray structures with the tethered fragments show that the subsite-binding interactions are similar to those observed with the original small molecule. Moreover, the adaptive subsite tethered many more compounds than did the rigid one. Thus, the adaptive nature of a protein-protein interface provides sites for small molecules to bind and underscores the challenge of applying structure-based design strategies that cannot accurately predict a dynamic protein surface. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1M4A 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 MPE and GOL as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http:// | + | 1M4A 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=MPE:'>MPE</scene> and <scene name='pdbligand=GOL:'>GOL</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1M4A OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Arkin, M | + | [[Category: Arkin, M A.]] |
| - | [[Category: Braisted, A | + | [[Category: Braisted, A C.]] |
| - | [[Category: DeLano, W | + | [[Category: DeLano, W L.]] |
[[Category: Hyde, J.]] | [[Category: Hyde, J.]] | ||
| - | [[Category: Luong, T | + | [[Category: Luong, T N.]] |
| - | [[Category: McDowell, R | + | [[Category: McDowell, R S.]] |
| - | [[Category: Oslob, J | + | [[Category: Oslob, J D.]] |
[[Category: Randal, M.]] | [[Category: Randal, M.]] | ||
| - | [[Category: Raphael, D | + | [[Category: Raphael, D R.]] |
[[Category: Taylor, L.]] | [[Category: Taylor, L.]] | ||
[[Category: Wang, J.]] | [[Category: Wang, J.]] | ||
| - | [[Category: Wells, J | + | [[Category: Wells, J A.]] |
[[Category: GOL]] | [[Category: GOL]] | ||
[[Category: MPE]] | [[Category: MPE]] | ||
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[[Category: small molecule complex]] | [[Category: small molecule complex]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 13:51:15 2008'' |
Revision as of 11:51, 21 February 2008
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Crystal Structure of Human Interleukin-2 Y31C Covalently Modified at C31 with (1H-Indol-3-yl)-(2-mercapto-ethoxyimino)-acetic acid
Contents |
Overview
Understanding binding properties at protein-protein interfaces has been limited to structural and mutational analyses of natural binding partners or small peptides identified by phage display. Here, we present a high-resolution analysis of a nonpeptidyl small molecule, previously discovered by medicinal chemistry [Tilley, J. W., et al. (1997) J. Am. Chem. Soc. 119, 7589-7590], which binds to the cytokine IL-2. The small molecule binds to the same site that binds the IL-2 alpha receptor and buries into a groove not seen in the free structure of IL-2. Comparison of the bound and several free structures shows this site to be composed of two subsites: one is rigid, and the other is highly adaptive. Thermodynamic data suggest the energy barriers between these conformations are low. The subsites were dissected by using a site-directed screening method called tethering, in which small fragments were captured by disulfide interchange with cysteines introduced into IL-2 around these subsites. X-ray structures with the tethered fragments show that the subsite-binding interactions are similar to those observed with the original small molecule. Moreover, the adaptive subsite tethered many more compounds than did the rigid one. Thus, the adaptive nature of a protein-protein interface provides sites for small molecules to bind and underscores the challenge of applying structure-based design strategies that cannot accurately predict a dynamic protein surface.
Disease
Known disease associated with this structure: Severe combined immunodeficiency due to IL2 deficiency OMIM:[147680]
About this Structure
1M4A is a Single protein structure of sequence from Homo sapiens with and as ligands. Full crystallographic information is available from OCA.
Reference
Binding of small molecules to an adaptive protein-protein interface., Arkin MR, Randal M, DeLano WL, Hyde J, Luong TN, Oslob JD, Raphael DR, Taylor L, Wang J, McDowell RS, Wells JA, Braisted AC, Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1603-8. Epub 2003 Feb 11. PMID:12582206
Page seeded by OCA on Thu Feb 21 13:51:15 2008
Categories: Homo sapiens | Single protein | Arkin, M A. | Braisted, A C. | DeLano, W L. | Hyde, J. | Luong, T N. | McDowell, R S. | Oslob, J D. | Randal, M. | Raphael, D R. | Taylor, L. | Wang, J. | Wells, J A. | GOL | MPE | Cytokine | Four-helix bundle | Small molecule complex
