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@article{White:2023:10.1016/j.chembiol.2023.06.021,
author = {White, MEH and Gil, J and Tate, EW},
doi = {10.1016/j.chembiol.2023.06.021},
journal = {Cell Chemical Biology},
pages = {828--838.e4},
title = {Proteome-wide structural analysis identifies warhead- and coverage-specific biases in cysteine-focused chemoproteomics},
url = {http://dx.doi.org/10.1016/j.chembiol.2023.06.021},
volume = {30},
year = {2023}
}
TY - JOUR
AB - Covalent drug discovery has undergone a resurgence over the past two decades and reactive cysteine profiling has emerged in parallel as a platform for ligand discovery through on- and off-target profiling; however, the scope of this approach has not been fully explored at the whole-proteome level. We combined AlphaFold2-predicted side-chain accessibilities for >95% of the human proteome with a meta-analysis of eighteen public cysteine profiling datasets, totaling 44,187 unique cysteine residues, revealing accessibility biases in sampled cysteines primarily dictated by warhead chemistry. Analysis of >3.5 million cysteine-fragment interactions further showed that hit elaboration and optimization drives increased bias against buried cysteine residues. Based on these data, we suggest that current profiling approaches cover a small proportion of potential ligandable cysteine residues and propose future directions for increasing coverage, focusing on high-priority residues and depth. All analysis and produced resources are freely available and extendable to other reactive amino acids.
AU - White,MEH
AU - Gil,J
AU - Tate,EW
DO - 10.1016/j.chembiol.2023.06.021
EP - 838
PY - 2023///
SN - 2451-9456
SP - 828
TI - Proteome-wide structural analysis identifies warhead- and coverage-specific biases in cysteine-focused chemoproteomics
T2 - Cell Chemical Biology
UR - http://dx.doi.org/10.1016/j.chembiol.2023.06.021
UR - http://hdl.handle.net/10044/1/105545
VL - 30
ER -
Prof. Ed Tate
GSK Chair in Chemical Biology
Department of Chemistry
Molecular Sciences Research Hub, White City Campus,
82 Wood Lane, London, W12 0BZ
e.tate@imperial.ac.uk
Tel: +44 (0)20 759 + ext 43752 or 45821