1y4c: Difference between revisions
New page: left|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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[[Image:1y4c.gif|left|200px]]<br /><applet load="1y4c" size=" | [[Image:1y4c.gif|left|200px]]<br /><applet load="1y4c" size="350" color="white" frame="true" align="right" spinBox="true" | ||
caption="1y4c, resolution 1.900Å" /> | caption="1y4c, resolution 1.900Å" /> | ||
'''Designed Helical Protein fusion MBP'''<br /> | '''Designed Helical Protein fusion MBP'''<br /> | ||
==Overview== | ==Overview== | ||
An IL-4 antagonist was designed based on structural and biochemical | 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== | ==About this Structure== | ||
1Y4C is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http:// | 1Y4C is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1Y4C OCA]. | ||
==Reference== | ==Reference== | ||
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[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Akhavan, D.]] | [[Category: Akhavan, D.]] | ||
[[Category: Cunningham, B | [[Category: Cunningham, B C.]] | ||
[[Category: Forsyth, C | [[Category: Forsyth, C M.]] | ||
[[Category: LaPorte, S | [[Category: LaPorte, S L.]] | ||
[[Category: Miercke, L | [[Category: Miercke, L J.]] | ||
[[Category: Stroud, R | [[Category: Stroud, R M.]] | ||
[[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:// | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 16:01:37 2008'' | ||
Revision as of 17:01, 21 February 2008
|
Designed Helical Protein fusion MBP
OverviewOverview
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 StructureAbout this Structure
1Y4C is a Single protein structure of sequence from Escherichia coli. Full crystallographic information is available from OCA.
ReferenceReference
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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