Coiled-coil surface presentation: an efficient HIV gp41 binding interface mimic.
An efficient mimic of the gp41 N-terminal coiled-coil trimer is described. The native protein mediates fusion of viral and cellular membranes, and its function is critical for infectivity. A central event in this process is formation of a "trimer of hairpins" structure in which a C-terminal gp41 sequence binds to a hydrophobic groove on the N-terminal trimer surface. Inhibition of this interaction is a promising therapeutic strategy, but the isolated trimer is not a convenient screening target, since the exposed hydrophobic pocket causes aggregation and precipitation. The problem has been circumvented in several ways such as attachment of auxiliary scaffolding elements or covalent subunit tethering. Here we report a more efficient approach, in which purely peptidic systems comparable in size to the native trimer display the expected specificity for the C-terminal ligand. Steric matching of 2:1 alanine/cyclohexylalanine core layers promotes formation of a 1:1:1 heterotrimer, whose surface interhelical interfaces can be uniquely controlled. Two of these interfaces contain solubilizing Glu/Lys pairs, while the third presents the gp41 interface. The model system binds the C-terminal peptide, while a control complex with only half the interface does not. A variety of biophysical methods are used to characterize the complex. The ability to control complex stoichiometry with only interior core residues should permit formation of any such interface, and extension to other viral systems is underway.
Department of Chemistry, Colorado State University, Fort Collins, CO 80523, USA.
Nathan A
NA
Schnarr
Alan J
AJ
Kennan
D000595:Amino Acid Sequence; D040761:Biomimetic Materials / Q000737:chemistry* / Q000378:metabolism; D002942:Circular Dichroism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D013499:Surface Properties
D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments