Allosteric communication between distant sites in proteins is central to biological regulation and underlies the efficacy of many drugs. Allostery allows proteins to function as molecular switches, with their activities controlled by ligand binding, covalent modifications, and mutations outside their active sites. Allosteric maps have been constructed for several proteins, but these all quantify regulation of a single site in each protein. How the allosteric maps of different sites compare is unclear. Here, we address this question by charting complete allosteric maps for two structurally distant binding sites in the oncoprotein KRAS. Unexpectedly, these maps reveal three different forms of allosteric control, that we term coupled, anti-coupled and independent allostery. Allostery in this small protein is therefore complex and multimodal. The co-existence of multiple allosteric networks in a single-domain protein has important conceptual implications and, if widespread, may allow the development of new classes of therapeutics that not only modulate targets but also tune their functional outputs.
Ma, Y., Jin, Q., Lehner, B., Weng, C.
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