Computation-guided backbone grafting of a discontinuous motif onto a protein scaffold

TitleComputation-guided backbone grafting of a discontinuous motif onto a protein scaffold
Publication TypeJournal Article
Year of Publication2011
AuthorsAzoitei, M. L., Correia B. E., Ban Y. - E. A., Carrico C., Kalyuzhniy O., Chen L., Schroeter A., Huang P. - S., McLellan J. S., Kwong P. D., Baker D., Strong R. K., & Schief W. R.
JournalScience
Volume334
Issue6054
Pagination373-6
Date Published2011 Oct 21
ISSN1095-9203
KeywordsAlgorithms, Amino Acid Motifs, Amino Acid Sequence, Antibodies, Monoclonal, Antibodies, Neutralizing, Antibody Affinity, Antibody Specificity, Antigens, CD4, Collaborative Publication, Computational Biology, Computer Simulation, Crystallography, X-Ray, Epitopes, HIV Antibodies, HIV Envelope Protein gp120, Models, Molecular, Molecular Mimicry, Molecular Sequence Data, Mutagenesis, Protein Conformation, Protein Engineering, Protein Interaction Domains and Motifs, Surface Plasmon Resonance
Abstract

The manipulation of protein backbone structure to control interaction and function is a challenge for protein engineering. We integrated computational design with experimental selection for grafting the backbone and side chains of a two-segment HIV gp120 epitope, targeted by the cross-neutralizing antibody b12, onto an unrelated scaffold protein. The final scaffolds bound b12 with high specificity and with affinity similar to that of gp120, and crystallographic analysis of a scaffold bound to b12 revealed high structural mimicry of the gp120-b12 complex structure. The method can be generalized to design other functional proteins through backbone grafting.

Alternate JournalScience
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