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Computation-Guided Backbone Grafting of a Discontinuous Motif onto a Protein Scaffold

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Science  21 Oct 2011:
Vol. 334, Issue 6054, pp. 373-376
DOI: 10.1126/science.1209368

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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.

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