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| [[Image:1y4c.gif|left|200px]] | | {{Seed}} |
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| {{STRUCTURE_1y4c| PDB=1y4c | SCENE= }} | | {{STRUCTURE_1y4c| PDB=1y4c | SCENE= }} |
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| '''Designed Helical Protein fusion MBP'''
| | ===Designed Helical Protein fusion MBP=== |
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| ==Overview==
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| 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.
| | The line below this paragraph, {{ABSTRACT_PUBMED_15684085}}, adds the Publication Abstract to the page |
| | (as it appears on PubMed at http://www.pubmed.gov), where 15684085 is the PubMed ID number. |
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| | {{ABSTRACT_PUBMED_15684085}} |
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| ==About this Structure== | | ==About this Structure== |
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| [[Category: De novo designed helical protein]] | | [[Category: De novo designed helical protein]] |
| [[Category: Maltose binding protein fusion]] | | [[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 Mon Jul 28 11:24:03 2008'' |
