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| {{STRUCTURE_1m4b| PDB=1m4b | SCENE= }} | | {{STRUCTURE_1m4b| PDB=1m4b | SCENE= }} |
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| '''Crystal Structure of Human Interleukin-2 K43C Covalently Modified at C43 with 2-[2-(2-Cyclohexyl-2-guanidino-acetylamino)-acetylamino]-N-(3-mercapto-propyl)-propionamide'''
| | ===Crystal Structure of Human Interleukin-2 K43C Covalently Modified at C43 with 2-[2-(2-Cyclohexyl-2-guanidino-acetylamino)-acetylamino]-N-(3-mercapto-propyl)-propionamide=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_12582206}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 12582206 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_12582206}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: Four-helix bundle]] | | [[Category: Four-helix bundle]] |
| [[Category: Small molecule complex]] | | [[Category: Small molecule complex]] |
| ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 00:36:44 2008'' | | |
| | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jul 2 23:10:35 2008'' |