1y4c
From Proteopedia
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'''Designed Helical Protein fusion MBP''' | '''Designed Helical Protein fusion MBP''' | ||
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[[Category: Miercke, L J.]] | [[Category: Miercke, L J.]] | ||
[[Category: Stroud, R M.]] | [[Category: Stroud, R M.]] | ||
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| - | [[Category: | + | [[Category: Maltose binding protein fusion]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sat May 3 15:51:51 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 12:51, 3 May 2008
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 Page seeded by OCA on Sat May 3 15:51:51 2008
