Computation-guided backbone grafting of a discontinuous motif onto a protein scaffold
|Title||Computation-guided backbone grafting of a discontinuous motif onto a protein scaffold|
|Publication Type||Journal Article|
|Year of Publication||2011|
|Authors||Azoitei, 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.|
|Date Published||2011 Oct 21|
|Keywords||Algorithms, 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|
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.