TY - JOUR
T1 - Principles for designing proteins with cavities formed by curved b sheets
AU - Marcos, Enrique
AU - Basanta, Benjamin
AU - Chidyausiku, Tamuka M.
AU - Tang, Yuefeng
AU - Oberdorfer, Gustav
AU - Liu, Gaohua
AU - Swapna, G. V.T.
AU - Guan, Rongjin
AU - Silva, Daniel Adriano
AU - Dou, Jiayi
AU - Pereira, Jose Henrique
AU - Xiao, Rong
AU - Sankaran, Banumathi
AU - Zwart, Peter H.
AU - Montelione, Gaetano T.
AU - Baker, David
N1 - Funding Information:
Work carried out at the Baker laboratory was supported by the Howard Hughes Medical Institute and the Defense Threat Reduction Agency (funding HDTRA 1-11-1-0041). X-ray diffraction data were collected at the National Synchrotron Light Source with beamline X4C [Brookhaven National Laboratory, Upton, NY, U.S. Department of Energy (DOE)] and the Advance Light Source (Lawrence Berkeley National Laboratory, Berkeley, CA, DOE). The Berkeley Center for Structural Biology is supported in part by the NIH; National Institute of General Medical Sciences (NIGMS), NIH; and the Howard Hughes Medical Institute. The Advanced Light Source is supported by the Director, Office of Science, Office of Basic Energy Sciences, of the DOE under contract no. DE-AC02- 05CH11231. E.M. was supported by a Marie Curie International Outgoing Fellowship (FP7-PEOPLE-2011-IOF 298976). IRB Barcelona is the recipient of a Severo Ochoa Award of Excellence from the Ministry of Economy, Industry, and Competitiveness (Government of Spain). G.O. was supported by a Marie Curie International Outgoing Fellowship (332094 ASR-CompEnzDes FP7-PEOPLE-2012-IOF). D.-A.S. is a Latin American PEW postdoctoral fellow and Mexican National Council of Science and Technology (CONACYT) postdoctoral fellow and acknowledges their support. This work was supported as a Community Outreach Activity of NIGMS Protein Structure Initiative grant U54 GM094597 (to G.T.M).
PY - 2017/1/13
Y1 - 2017/1/13
N2 - Active sites and ligand-binding cavities in native proteins are often formed by curved b sheets, and the ability to control b-sheet curvature would allow design of binding proteins with cavities customized to specific ligands.Toward this end, we investigated the mechanisms controlling β-sheet curvature by studying the geometry of β sheets in naturally occurring protein structures and folding simulations.The principles emerging from this analysis were used to design, de novo, a series of proteins with curved β sheets topped with a helices. Nuclear magnetic resonance and crystal structures of the designs closely match the computational models, showing that β-sheet curvature can be controlled with atomic-level accuracy. Our approach enables the design of proteins with cavities and provides a route to custom design ligand-binding and catalytic sites.
AB - Active sites and ligand-binding cavities in native proteins are often formed by curved b sheets, and the ability to control b-sheet curvature would allow design of binding proteins with cavities customized to specific ligands.Toward this end, we investigated the mechanisms controlling β-sheet curvature by studying the geometry of β sheets in naturally occurring protein structures and folding simulations.The principles emerging from this analysis were used to design, de novo, a series of proteins with curved β sheets topped with a helices. Nuclear magnetic resonance and crystal structures of the designs closely match the computational models, showing that β-sheet curvature can be controlled with atomic-level accuracy. Our approach enables the design of proteins with cavities and provides a route to custom design ligand-binding and catalytic sites.
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U2 - 10.1126/science.aah7389
DO - 10.1126/science.aah7389
M3 - Article
C2 - 28082595
AN - SCOPUS:85009786943
SN - 0036-8075
VL - 355
JO - Science
JF - Science
IS - 6321
M1 - 6321
ER -