BMC Biophys 2014 12;7. Epub 2014 Aug 12.
Department of Physics, University of Cyprus, PO 20537, CY1678 Nicosia, Cyprus.
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Mol Biosyst 2016 04;12(5):1586-99
Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology, Bhubaneswar, Odisha 751007, India.
The C5a receptor (C5aR) is a pharmacologically important G-protein coupled receptor (GPCR) that interacts with (h)C5a, by recruiting both the "orthosteric" sites (site1 at the N-terminus and site2 at the ECS, extra cellular surface) on C5aR in a two site-binding model. However, the complex pharmacological landscape and the distinguishing chemistry operating either at the "orthosteric" site1 or at the functionally important "orthosteric" site2 of C5aR are still not clear, which greatly limits the understanding of C5aR pharmacology. One of the major bottlenecks is the lack of an experimental structure or a refined model structure of C5aR with appropriately defined active sites. Read More
Nat Struct Mol Biol 2018 Jun 4;25(6):472-481. Epub 2018 Jun 4.
Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
The C5a receptor (C5aR) is a G-protein-coupled receptor (GPCR) that can induce strong inflammatory response to the anaphylatoxin C5a. Targeting C5aR has emerged as a novel anti-inflammatory therapeutic method. However, developing potent C5aR antagonists as drugs has proven difficult. Read More
Biopolymers 2008 ;90(6):803-15
Department of Chemistry, University of California, Riverside, CA 92521, USA.
The cyclic hexapeptide Ac(0)-Phe(1)-[Orn(2)-Pro(3)-dCha(4)-Trp(5)-Arg(6)] (the square brackets denote cyclization) is a potent antagonist against C5a (the a-fragment of complement protein C5) binding to C5a receptor (C5aR) and an excellent candidate to become a therapeutic agent against diseases that involve unregulated activation of the complement system. We present the solution structure determination of this cyclic C5aR peptide antagonist (cC5aR-pa), using nuclear magnetic resonance (NMR) data and restrained molecular dynamics-based simulated annealing in torsion angle space with NMR-derived distance and torsion angle restraints. The calculated NMR ensemble of structures demonstrates the presence of a predominant conformation of a distorted type II' beta-turn in the segment Pro(3)-dCha(4)-Trp(5)-Arg(6). Read More
J Biol Chem 2005 May 20;280(18):17831-40. Epub 2005 Jan 20.
Academic Neurology Unit, University of Sheffield Medical School, Sheffield S10 2RX, United Kingdom.
The C terminus is responsible for all of the agonist activity of C5a at human C5a receptors (C5aRs). In this report we have mapped the ligand binding site on the C5aR using a series of agonist and antagonist peptide mimics of the C terminus of C5a as well as receptors mutated at putative interaction sites (Ile(116), Arg(175,) Arg(206), Glu(199), Asp(282), and Val(286)). Agonist peptide 1 (Phe-Lys-Pro-d-cyclohexylalanine-cyclohexylalanine-d-Arg) can be converted to an antagonist by substituting the bulkier Trp for cyclohexylalanine at position 5 (peptide 2). Read More