8UGW
Computational design of highly signaling active membrane receptors through de novo solvent-mediated allosteric networks
Summary for 8UGW
| Entry DOI | 10.2210/pdb8ugw/pdb |
| Descriptor | Endolysin,Adenosine receptor A2a, 2-[P-(2-CARBOXYETHYL)PHENYLETHYL-AMINO]-5'-N-ETHYLCARBOXAMIDO ADENOSINE (2 entities in total) |
| Functional Keywords | the adenosine a2a receptor, membrane protein |
| Biological source | Tequatrovirus T4 More |
| Total number of polymer chains | 1 |
| Total formula weight | 53188.23 |
| Authors | Wang, J.,Chen, K.Y.,Lai, J.K.,Russell, A.M.,Conners, K.,Rutter, M.E.,Condon, B.,Tung, F.,Kodandapani, L.,Chau, B.,Zhao, X.,Benach, J.,Baker, K.,Hembre, E.J.,Barth, P. (deposition date: 2023-10-06, release date: 2024-12-18, Last modification date: 2025-03-12) |
| Primary citation | Chen, K.M.,Lai, J.K.,Rudden, L.S.P.,Wang, J.,Russell, A.M.,Conners, K.,Rutter, M.E.,Condon, B.,Tung, F.,Kodandapani, L.,Chau, B.,Zhao, X.,Benach, J.,Baker, K.,Hembre, E.J.,Barth, P. Computational design of highly signalling-active membrane receptors through solvent-mediated allosteric networks. Nat.Chem., 17:429-438, 2025 Cited by PubMed 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. PubMed: 39849110DOI: 10.1038/s41557-024-01719-2 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.9 Å) |
Structure validation
Download full validation report
