1y4c
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(New page: 200px<br /><applet load="1y4c" size="450" color="white" frame="true" align="right" spinBox="true" caption="1y4c, resolution 1.900Å" /> '''Designed Helical Pr...)
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Revision as of 04:26, 21 November 2007
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Designed Helical Protein fusion MBP
Overview
An IL-4 antagonist was designed based on structural and biochemical, analysis of unbound IL-4 and IL-4 in complex with its high-affinity, receptor (IL-4Ralpha). Our design strategy sought to capture a, protein-protein interaction targeting the high affinity that IL-4 has for, IL-4Ralpha. This strategy has impact due to the potential relevance of, IL-4Ralpha as a drug target in the treatment of asthma. To mimic the IL-4, binding surface, critical side chains for receptor binding were, identified, and these side chains were transplanted onto a previously, characterized, de novo-designed four-helix protein called designed helical, protein 1 (DHP-1). This first-generation design resolved the ambiguity, previously described for the connectivity between helices in DHP-1 and, resulted in a protein capable of binding to IL-4Ralpha. The, second-generation antagonist was based upon further molecular modeling, and it succeeded in binding IL-4Ralpha better than the first-generation., This protein, termed DHP-14-AB, yielded a protein with a cooperative, unfolding transition (DeltaGu0=8.1 kcal/mol) and an IC50 of 27 microM when, in competition with IL-4 whereas DHP-1 had no affinity for IL-4Ralpha. The, crystal structure of DHP-14-AB was determined to 1.9-A resolution and was, compared with IL-4. This comparison revealed how design strategies, targeting protein-protein interactions require high-resolution 3D data and, the incorporation of orientation-specific information at the level of, side-chains and secondary structure element interactions.
About this Structure
1Y4C is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
Reference
De novo design of an IL-4 antagonist and its structure at 1.9 A., Laporte SL, Forsyth CM, Cunningham BC, Miercke LJ, Akhavan D, Stroud RM, Proc Natl Acad Sci U S A. 2005 Feb 8;102(6):1889-94. Epub 2005 Jan 31. PMID:15684085
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