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Protein structure determination using metagenome sequence data

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Science  20 Jan 2017:
Vol. 355, Issue 6322, pp. 294-298
DOI: 10.1126/science.aah4043

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Filling in the protein fold picture

Fewer than a third of the 14,849 known protein families have at least one member with an experimentally determined structure. This leaves more than 5000 protein families with no structural information. Protein modeling using residue-residue contacts inferred from evolutionary data has been successful in modeling unknown structures, but it requires large numbers of aligned sequences. Ovchinnikov et al. augmented such sequence alignments with metagenome sequence data (see the Perspective by Söding). They determined the number of sequences required to allow modeling, developed criteria for model quality, and, where possible, improved modeling by matching predicted contacts to known structures. Their method predicted quality structural models for 614 protein families, of which about 140 represent newly discovered protein folds.

Science, this issue p. 294; see also p. 248

Abstract

Despite decades of work by structural biologists, there are still ~5200 protein families with unknown structure outside the range of comparative modeling. We show that Rosetta structure prediction guided by residue-residue contacts inferred from evolutionary information can accurately model proteins that belong to large families and that metagenome sequence data more than triple the number of protein families with sufficient sequences for accurate modeling. We then integrate metagenome data, contact-based structure matching, and Rosetta structure calculations to generate models for 614 protein families with currently unknown structures; 206 are membrane proteins and 137 have folds not represented in the Protein Data Bank. This approach provides the representative models for large protein families originally envisioned as the goal of the Protein Structure Initiative at a fraction of the cost.

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