Submolecular probing of the complement C5a receptor–ligand binding reveals a cooperative two-site binding mechanism
(2020) Communications Biology — Vol. 3, n° 1, p. 786 (2020)
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- Authors
Koehler, Melanie 
- Abstract
- A current challenge to produce effective therapeutics is to accurately determine the location of the ligand-biding site and to characterize its properties. So far, the mechanisms underlying the functional activation of cell surface receptors by ligands with a complex binding mechanism remain poorly understood due to a lack of suitable nanoscopic methods to study them in their native environment. Here, we elucidated the ligand-binding mechanism of the human G protein-coupled C5a receptor (C5aR). We discovered for the first time a cooperativity between the two orthosteric binding sites. We found that the N-terminus C5aR serves as a kinetic trap, while the transmembrane domain acts as the functional site and both contributes to the overall high-affinity interaction. In particular, Asp282 plays a key role in ligand binding thermodynamics, as revealed by atomic force microscopy and steered molecular dynamics simulation. Our findings provide a new structural basis for the functional and mechanistic understanding of the GPCR family that binds large macromolecular ligands.
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Citations
Dumitru, A.-C., Deepak, R. N. V. K., Liu, H., Koehler, M., Zhang, C., Fan, H., & Alsteens, D. (2020). Submolecular probing of the complement C5a receptor–ligand binding reveals a cooperative two-site binding mechanism. Communications Biology, 3(1), 786. https://doi.org/10.1038/s42003-020-01518-8 (Original work published 2020)