NDLI: A de novo protein binding pair by computational design and directed evolution

Content Provider	PubMed Central
Author	John, Karanicolas Corn, Jacob E. Chen, Irwin Joachimiak, Lukasz A. Dym, Orly Peck, Sun H. Albeck, Shira Unger, Tamar Hu, Wenxin Liu, Gaohua Delbecq, Scott Gaetano, Montelione Spiegel, Clint Liu, David R. Baker, David
Copyright Year	2011
Abstract	The de novo design of protein-protein interfaces is a stringent test of our understanding of the principles underlying protein-protein interactions and would enable new approaches to biological and medical challenges. Here we describe a novel motif-based method to computationally design protein-protein complexes with native-like interface composition and interaction density. Using this method we designed a pair of proteins, Prb and Pdar, that heterodimerize with a Kd of 130 nM, 1,000-fold tighter than any previously designed de novo protein-protein complex. Directed evolution identified two point mutations that improve affinity to 180 pM. Crystal structures of complexes containing designed and evolved proteins reveal binding is entirely through the designed interface, making use of specific designed interactions. Surprisingly, in the evolved complex one of the partners is rotated 180 degrees relative to the design model. This work demonstrates that current understanding of protein-protein interfaces is sufficient to rationally design interfaces de novo, and underscores remaining challenges.
Related Links	http://dx.doi.org/10.1016/j.molcel.2011.03.010
Ending Page	260
Page Count	11
Starting Page	250
File Format	PDF
ISSN	10972765
e-ISSN	10974164
Journal	Molecular cell
Issue Number	2
Volume Number	42
Language	English
Publisher Date	2011-04-01
Access Restriction	Open
Subject Keyword	Cell Biology Molecular Biology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Cell Biology Molecular Biology

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