Submolecular probing of the complement C5a receptor-ligand binding reveals a cooperative two-site binding mechanism. 2020

Andra C Dumitru, and R N V Krishna Deepak, and Heng Liu, and Melanie Koehler, and Cheng Zhang, and Hao Fan, and David Alsteens
Université catholique de Louvain, Louvain Institute of Biomolecular Science and Technology, 1348, Louvain-la-Neuve, Belgium.

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.

UI MeSH Term Description Entries
D007700 Kinetics The rate dynamics in chemical or physical systems.
D008024 Ligands A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed) Ligand
D008051 Lipid Bilayers Layers of lipid molecules which are two molecules thick. Bilayer systems are frequently studied as models of biological membranes. Bilayers, Lipid,Bilayer, Lipid,Lipid Bilayer
D010456 Peptides, Cyclic Peptides whose amino acid residues are linked together forming a circular chain. Some of them are ANTI-INFECTIVE AGENTS; some are biosynthesized non-ribosomally (PEPTIDE BIOSYNTHESIS, NON-RIBOSOMAL). Circular Peptide,Cyclic Peptide,Cyclic Peptides,Cyclopeptide,Orbitide,Circular Peptides,Cyclopeptides,Orbitides,Peptide, Circular,Peptide, Cyclic,Peptides, Circular
D011485 Protein Binding The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments. Plasma Protein Binding Capacity,Binding, Protein
D002462 Cell Membrane The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells. Plasma Membrane,Cytoplasmic Membrane,Cell Membranes,Cytoplasmic Membranes,Membrane, Cell,Membrane, Cytoplasmic,Membrane, Plasma,Membranes, Cell,Membranes, Cytoplasmic,Membranes, Plasma,Plasma Membranes
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D001665 Binding Sites The parts of a macromolecule that directly participate in its specific combination with another molecule. Combining Site,Binding Site,Combining Sites,Site, Binding,Site, Combining,Sites, Binding,Sites, Combining
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013816 Thermodynamics A rigorously mathematical analysis of energy relationships (heat, work, temperature, and equilibrium). It describes systems whose states are determined by thermal parameters, such as temperature, in addition to mechanical and electromagnetic parameters. (From Hawley's Condensed Chemical Dictionary, 12th ed) Thermodynamic

Related Publications

Andra C Dumitru, and R N V Krishna Deepak, and Heng Liu, and Melanie Koehler, and Cheng Zhang, and Hao Fan, and David Alsteens
November 2001, Biochemistry,
Andra C Dumitru, and R N V Krishna Deepak, and Heng Liu, and Melanie Koehler, and Cheng Zhang, and Hao Fan, and David Alsteens
July 1994, Molecular immunology,
Andra C Dumitru, and R N V Krishna Deepak, and Heng Liu, and Melanie Koehler, and Cheng Zhang, and Hao Fan, and David Alsteens
October 1993, Journal of immunology (Baltimore, Md. : 1950),
Andra C Dumitru, and R N V Krishna Deepak, and Heng Liu, and Melanie Koehler, and Cheng Zhang, and Hao Fan, and David Alsteens
January 1989, Proceedings of the National Academy of Sciences of the United States of America,
Andra C Dumitru, and R N V Krishna Deepak, and Heng Liu, and Melanie Koehler, and Cheng Zhang, and Hao Fan, and David Alsteens
July 1992, Journal of leukocyte biology,
Andra C Dumitru, and R N V Krishna Deepak, and Heng Liu, and Melanie Koehler, and Cheng Zhang, and Hao Fan, and David Alsteens
January 1999, The Journal of biological chemistry,
Andra C Dumitru, and R N V Krishna Deepak, and Heng Liu, and Melanie Koehler, and Cheng Zhang, and Hao Fan, and David Alsteens
October 2005, Journal of molecular biology,
Andra C Dumitru, and R N V Krishna Deepak, and Heng Liu, and Melanie Koehler, and Cheng Zhang, and Hao Fan, and David Alsteens
July 1995, The Journal of biological chemistry,
Andra C Dumitru, and R N V Krishna Deepak, and Heng Liu, and Melanie Koehler, and Cheng Zhang, and Hao Fan, and David Alsteens
November 2006, Molecular pharmacology,
Andra C Dumitru, and R N V Krishna Deepak, and Heng Liu, and Melanie Koehler, and Cheng Zhang, and Hao Fan, and David Alsteens
July 1994, Journal of cellular biochemistry,
Copied contents to your clipboard!