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bioRxiv · 10.1101/182287

Functional characterization of 3D-protein structures informed by human genetic diversity

Hicks, M.·Bartha, I.·di Iulio, J.·Abagyan, R.·Venter, J. C.·Telenti, A.
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Abstract

Sequence variation data of the human proteome can be used to analyze 3-dimensional (3D) protein structures to derive functional insights. We used genetic variant data from nearly 150,000 individuals to analyze 3D positional conservation in 4,390 protein structures using 481,708 missense and 264,257 synonymous variants. Sixty percent of protein structures harbor at least one intolerant 3D site as defined by significant depletion of observed over expected missense variation. We established an Angstrom-scale distribution of annotated pathogenic missense variants and showed that they accumulate in proximity to the most intolerant 3D sites. Structural intolerance data correlated with experimental functional read-outs in vitro. The 3D structural intolerance analysis revealed characteristic features of ligand binding pockets, orthosteric and allosteric sites. The identification of novel functional 3D sites based on human genetic data helps to validate, rank or predict drug target binding sites in vivo.

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Hicks, M., Bartha, I., di Iulio, J., Abagyan, R., Venter, J. C., Telenti, A.. 2017-08-29. Functional characterization of 3D-protein structures informed by human genetic diversity. https://doi.org/10.1101/182287

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