Affiliation:
1. Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94158, USA.
Abstract
A new tool in the protein design toolbox
Protein design can compute protein folds from first principles. However, designing new proteins that are functional remains challenging, in part because designing binding interactions requires simultaneous optimization of protein sequence and protein-ligand conformation. Polizzi and DeGrado designed proteins from scratch that bind a small-molecule drug (see the Perspective by Peacock). They introduced a new structural element called a van der Mer (vdM), which tracks the orientation of a chemical group relative to the backbone of a contacting residue. Assuming proteins bind ligands using interactions similar to intraprotein packing, they determined statistically preferred vdMs from a large set of structures in the Protein Data Bank. By including weighted vdMs in their computations, they designed two of six de novo proteins that bind the drug apixaban. A drug-protein x-ray crystal structure confirmed the designed model.
Science
, this issue p.
1227
; see also p.
1166
Funder
National Science Foundation
National Institutes of Health
National Institute of General Medical Sciences
Air Force Office of Scientific Research
Publisher
American Association for the Advancement of Science (AAAS)
Cited by
58 articles.
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