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

被引：168

作者：

Azoitei, Mihai L. ^{[1
]}

Correia, Bruno E. ^{[1
,2
]}

Ban, Yih-En Andrew ^{[1
]}

Carrico, Chris ^{[1
,3
]}

Kalyuzhniy, Oleksandr ^{[1
]}

Chen, Lei ^{[4
]}

Schroeter, Alexandria ^{[1
]}

Huang, Po-Ssu ^{[1
]}

McLellan, Jason S. ^{[4
]}

Kwong, Peter D. ^{[4
]}

Baker, David ^{[1
,5
]}

Strong, Roland K. ^{[3
]}

Schief, William R. ^{[1
,6
,7
]}

机构：

[1] Univ Washington, Dept Biochem, Seattle, WA 98195 USA

[2] Inst Gulbenkian Ciencias, PhD Program Computat Biol, Oeiras, Portugal

[3] Fred Hutchinson Canc Res Ctr, Div Basic Sci, Seattle, WA 98104 USA

[4] NIAID, Vaccine Res Ctr, Bethesda, MD 20892 USA

[5] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA

[6] Scripps Res Inst, IAVI Neutralizing Antibody Ctr, La Jolla, CA 92037 USA

[7] Scripps Res Inst, Dept Immunol & Microbial Sci, La Jolla, CA 92037 USA

来源：

SCIENCE | 2011年 / 334卷 / 6054期

关键词：

EPITOPE-SCAFFOLDS; HIV-1; GP120; DESIGN; ANTIBODIES; NEUTRALIZATION; SITE;

D O I：

10.1126/science.1209368

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：373 / 376

页数：4

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