1M4C

Crystal Structure of Human Interleukin-2

Summary for 1M4C

• Entry DOI: 10.2210/pdb1m4c/pdb
• Related: 1M47 1M48 1M49 1M4A 1M4B
• Descriptor: interleukin-2 (1 entity in total)
• Functional Keywords: cytokine, four-helix bundle
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P60568
• Total number of polymer chains: 2
• Total formula weight: 30871.96

Authors

Arkin, M.A.,Randal, M.,DeLano, W.L.,Hyde, J.,Luong, T.N.,Oslob, J.D.,Raphael, D.R.,Taylor, L.,Wang, J.,McDowell, R.S.,Wells, J.A.,Braisted, A.C. (deposition date: 2002-07-02, release date: 2002-07-31, Last modification date: 2017-10-11)

Primary citation

Arkin, M.A.,Randal, M.,DeLano, W.L.,Hyde, J.,Luong, T.N.,Oslob, J.D.,Raphael, D.R.,Taylor, L.,Wang, J.,McDowell, R.S.,Wells, J.A.,Braisted, A.C.
Binding of small molecules to an adaptive protein-protein interface
Proc.Natl.Acad.Sci.USA, 100:1603-1608, 2003

PubMed Abstract: 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.

PubMed: 12582206
DOI: 10.1073/pnas.252756299

Experimental method

X-RAY DIFFRACTION (2.4 Å)