The goal of this proposal is further understanding of molecular recognition events on coiled coil surfaces. Although considerable experimentation has been directed towards the assembly of coiled coil structures themselves (e.g. sequence requirements, impact of hydrophobic core packing angles and residue identity, etc.), little attention has been paid to the design of structures that bind to preformed coiled coils. Recently, such interactions have taken on dramatic biological significance with the discovery that binding of certain viral proteins to the surface of homotrimeric coiled coils is required to accomplish fusion with target cell membranes, and hence infectivity. A broad range of viruses, with examples from numerous families, are now thought to employ very similar fusion mechanisms, all of which depend on a similar recognition event. Together they are responsible for numerous health issues, including AIDS, hemorrhagic fever, leukemia, and severe respiratory infection. In several cases, drug development on the basis of these interactions has already yielded effective therapeutics. To elucidate the underlying molecular recognition requirements of these interactions we will undertake to: (1) Establish efficient model systems for presentation of lentiviral helical interfaces (2) Examine the generality of lentiviral binding principles in modified contexts (3) Explore the interface of Human Respiratory Syncytial Virus (HRSV) (4) Examine binding demands of Simian Parainfluenza Virus 5 (SV5) (5) Determine the impact of significant binding surface modification in Ebola Virus (6) Investigate binding of nearly fully extended ligands in Human T-Cell Leukemia Virus (HTLV) sequences
| Diss, Maria L; Kennan, Alan J (2008) Heterotrimeric coiled coils with core residue urea side chains. J Org Chem 73:9752-5 |
| Schnarr, Nathan A; Kennan, Alan J (2004) Coiled-coil surface presentation: an efficient HIV gp41 binding interface mimic. J Am Chem Soc 126:10260-1 |
