Computational design of self-assembling cyclic protein homo-oligomers

被引:0
|
作者
Fallas, Jorge A. [1 ,2 ]
Ueda, George [1 ,2 ]
Sheffler, William [1 ,2 ]
Nguyen, Vanessa [2 ]
McNamara, Dan E. [3 ,7 ,8 ,9 ]
Sankaran, Banumathi [4 ]
Pereira, Jose Henrique [4 ,5 ]
Parmeggiani, Fabio [1 ,2 ]
Brunette, T. J. [1 ,2 ]
Cascio, Duilio [3 ]
Yeates, Todd R. [3 ]
Zwart, Peter [4 ]
Baker, David [1 ,2 ,6 ]
机构
[1] Univ Washington, Dept Biochem, Seattle, WA 98195 USA
[2] Univ Washington, Inst Prot Design, Seattle, WA 98195 USA
[3] Univ Calif Los Angeles, Dept Chem & Biochem, Los Angeles, CA 90095 USA
[4] Berkeley Ctr Struct Biol Mol Biophys & Integrated, Lawrence Berkeley Lab, Berkeley, CA 94720 USA
[5] Joint Bioenergy Inst, Emeryville, CA 94608 USA
[6] Univ Washington, Howard Hughes Med Inst, Seattle, WA 98195 USA
[7] St Jude Childrens Res Hosp, Dept Biol Struct, Memphis, TN 38105 USA
[8] St Jude Childrens Res Hosp, Dept Biol Chem, Memphis, TN 38105 USA
[9] St Jude Childrens Res Hosp, Dept Therapeut, Memphis, TN 38105 USA
基金
美国国家科学基金会; 美国国家卫生研究院;
关键词
DE-NOVO DESIGN; DOCKING; EVOLUTIONARY; PRINCIPLES; HOMODIMER; ASSOCIATION; SPECIFICITY; INTERFACES; SHAPE;
D O I
10.1038/NCHEM.2673
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Self-assembling cyclic protein homo-oligomers play important roles in biology, and the ability to generate custom homo-oligomeric structures could enable new approaches to probe biological function. Here we report a general approach to design cyclic homooligomers that employs a new residue-pair-transform method to assess the designability of a protein-protein interface. This method is sufficiently rapid to enable the systematic enumeration of cyclically docked arrangements of a monomer followed by sequence design of the newly formed interfaces. We use this method to design interfaces onto idealized repeat proteins that direct their assembly into complexes that possess cyclic symmetry. Of 96 designs that were characterized experimentally, 21 were found to form stable monodisperse homo-oligomers in solution, and 15 (four homodimers, six homotrimers, six homotetramers and one homopentamer) had solution small-angle X-ray scattering data consistent with the design models. X-ray crystal structures were obtained for five of the designs and each is very close to their corresponding computational model.
引用
收藏
页码:353 / 360
页数:8
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