@article{chen_computational_2025,
	title = {Computational design of highly signalling-active membrane receptors through solvent-mediated allosteric networks},
	issn = {1755-4330, 1755-4349},
	url = {https://www.nature.com/articles/s41557-024-01719-2},
	doi = {10.1038/s41557-024-01719-2},
	abstract = {Abstract
            Protein catalysis and allostery require the atomic-level orchestration and motion of residues and ligand, solvent and protein effector molecules. However, the ability to design protein activity through precise protein–solvent cooperative interactions has not yet been demonstrated. Here we report the design of 14 membrane receptors that catalyse G protein nucleotide exchange through diverse engineered allosteric pathways mediated by cooperative networks of intraprotein, protein–ligand and –solvent molecule interactions. Consistent with predictions, the designed protein activities correlated well with the level of plasticity of the networks at flexible transmembrane helical interfaces. Several designs displayed considerably enhanced thermostability and activity compared with related natural receptors. The most stable and active variant crystallized in an unforeseen signalling-active conformation, in excellent agreement with the design models. The allosteric network topologies of the best designs bear limited similarity to those of natural receptors and reveal an allosteric interaction space larger than previously inferred from natural proteins. The approach should prove useful for engineering proteins with novel complex protein binding, catalytic and signalling activities.},
	journaltitle = {Nature Chemistry},
	shortjournal = {Nat. Chem.},
	author = {Chen, K.-Y. M. and Lai, J. K. and Rudden, L. S. P. and Wang, J. and Russell, A. M. and Conners, K. and Rutter, M. E. and Condon, B. and Tung, F. and Kodandapani, L. and Chau, B. and Zhao, X. and Benach, J. and Baker, K. and Hembre, E. J. and Barth, P.},
	urldate = {2025-02-07},
	date = {2025-01-23},
	langid = {english},
}