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1m49
From Proteopedia
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|PDB= 1m49 |SIZE=350|CAPTION= <scene name='initialview01'>1m49</scene>, resolution 2.0Å | |PDB= 1m49 |SIZE=350|CAPTION= <scene name='initialview01'>1m49</scene>, resolution 2.0Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= <scene name='pdbligand=CMM:2-[2-(1-CARBAMIMIDOYL-PIPERIDIN-3-YL)-ACETYLAMINO]-3-{4-[2-(3-OXALYL-1H-INDOL-7-YL)ETHYL]-PHENYL}-PROPIONIC ACID METHYL ESTER'>CMM</scene> | + | |LIGAND= <scene name='pdbligand=CMM:2-[2-(1-CARBAMIMIDOYL-PIPERIDIN-3-YL)-ACETYLAMINO]-3-{4-[2-(3-OXALYL-1H-INDOL-7-YL)ETHYL]-PHENYL}-PROPIONIC+ACID+METHYL+ESTER'>CMM</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1m47|1M47]], [[1m48|1M48]], [[1m4a|1M4A]], [[1m4b|1M4B]], [[1m4c|1M4C]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1m49 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1m49 OCA], [http://www.ebi.ac.uk/pdbsum/1m49 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1m49 RCSB]</span> | ||
}} | }} | ||
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==Overview== | ==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. | 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:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=147680 147680]] | ||
==About this Structure== | ==About this Structure== | ||
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[[Category: Wang, J.]] | [[Category: Wang, J.]] | ||
[[Category: Wells, J A.]] | [[Category: Wells, J A.]] | ||
| - | [[Category: CMM]] | ||
[[Category: cytokine]] | [[Category: cytokine]] | ||
[[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 | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 22:11:03 2008'' |
Revision as of 19:11, 30 March 2008
| |||||||
| , resolution 2.0Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | |||||||
| Related: | 1M47, 1M48, 1M4A, 1M4B, 1M4C
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
Crystal Structure of Human Interleukin-2 Complexed with SP-1985
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.
About this Structure
1M49 is a Single protein structure of sequence from Homo sapiens. 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 Sun Mar 30 22:11:03 2008
