Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking

Tamamis, Phanourios, Kieslich, Chris A., Nikiforovich, Gregory V., Woodruff, Trent M., Morikis, Dimitrios and Archontis, Georgios (2014) Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking. BMC Biophysics, 7 1: 1-16. doi:10.1186/2046-1682-7-5


Author Tamamis, Phanourios
Kieslich, Chris A.
Nikiforovich, Gregory V.
Woodruff, Trent M.
Morikis, Dimitrios
Archontis, Georgios
Title Insights into the mechanism of C5aR inhibition by PMX53 via implicit solvent molecular dynamics simulations and docking
Journal name BMC Biophysics   Check publisher's open access policy
ISSN 2046-1682
Publication date 2014-08-12
Year available 2014
Sub-type Article (original research)
DOI 10.1186/2046-1682-7-5
Open Access Status DOI
Volume 7
Issue 1
Start page 1
End page 16
Total pages 16
Place of publication London, United Kingdom
Publisher BioMed Central
Language eng
Formatted abstract
Background

The complement protein C5a acts by primarily binding and activating the G-protein coupled C5a receptor C5aR (CD88), and is implicated in many inflammatory diseases. The cyclic hexapeptide PMX53 (sequence Ace-Phe-[Orn-Pro-dCha-Trp-Arg]) is a full C5aR antagonist of nanomolar potency, and is widely used to study C5aR function in disease.

Results

We construct for the first time molecular models for the C5aR:PMX53 complex without the a priori use of experimental constraints, via a computational framework of molecular dynamics (MD) simulations, docking, conformational clustering and free energy filtering. The models agree with experimental data, and are used to propose important intermolecular interactions contributing to binding, and to develop a hypothesis for the mechanism of PMX53 antagonism.

Conclusion

This work forms the basis for the design of improved C5aR antagonists, as well as for atomic-detail mechanistic studies of complement activation and function. Our computational framework can be widely used to develop GPCR-ligand structural models in membrane environments, peptidomimetics and other chemical compounds with potential clinical use.
Keyword Class A GPCR
C5aR
C5a
Complement system
Molecular dynamics
Docking
Implicit solvent
Membrane protein
Muscarinic acetylcholine receptor
Protein coupled receptors
Ligand binding site
Polymorphonuclear leukocytes
Biomolecular simulation
Extracellular loops
Cyclic antagonists
Complement
Compstatin
Anaphylatoxin
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Biomedical Sciences Publications
 
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