Abstract
Chemokine receptors are key G-protein-coupled receptors (GPCRs) that control cell migration in immune system responses, development of cardiovascular and central nervous systems, and numerous diseases. In particular, the CXCR4 chemokine receptor promotes metastasis, tumor growth and angiogenesis in cancers. CXCR4 is also used as one of the two co-receptors for T-tropic HIV-1 entry into host cells. Therefore, CXCR4 serves as an important therapeutic target for treating cancers and HIV infection. Apart from the CXCL12 endogenous peptide agonist, previous studies suggested that the first 17 amino acids of CXCL12 are sufficient to activate CXCR4. Two 17-residue peptides with positions 1–4 mutated to RSVM and ASLW functioned as super and partial agonists of CXCR4, respectively. However, the mechanism of peptide agonist binding in CXCR4 remains unclear. Here, we have investigated this mechanism through all-atom simulations using a novel Peptide Gaussian accelerated molecular dynamics (Pep-GaMD) method. The Pep-GaMD simulations have allowed us to explore representative binding conformations of each peptide and identify critical low-energy states of CXCR4 activated by the super versus partial peptide agonists. Our simulations have provided important mechanistic insights into peptide agonist binding in CXCR4, which are expected to facilitate rational design of new peptide modulators of CXCR4 and other chemokine receptors.
Highlights
Chemokine receptors are key G-protein-coupled receptors (GPCRs) which control cell migration during immune system responses, development of cardiovascular and central nervous systems, and in diseases including inflammation and cancer (Balkwill, 2004; Koelink et al, 2012)
All-atom simulations using the novel Pep-Gaussian accelerated MD (GaMD) method have been performed on the CXCR4 receptor bound to the ASLW, RSVM, 1–17wt, CXCL12 and vMIP-II peptides to refine the peptide-receptor complexes and capture the dynamic interactions between the peptides and CXCR4
CXCL12 bound CXCR4 was able to sample the Active conformational state, the probability appeared to be lower than that sampled by the 1–17 wt peptide agonist
Summary
Chemokine receptors are key G-protein-coupled receptors (GPCRs) which control cell migration during immune system responses, development of cardiovascular and central nervous systems, and in diseases including inflammation and cancer (Balkwill, 2004; Koelink et al, 2012). The CCR5 and CXCR4 chemokine receptors function as co-receptors that facilitate HIV entry into host cells (Wu et al, 2010; Qin et al, 2015; Zheng et al, 2017). Antagonists of the CCR5 receptor, named Maraviroc and Vicriviroc, have been used as clinical drugs that could block HIV entry and its replication (Tan et al, 2013). The primary endogenous chemokinebinding (orthosteric) site is conserved across different subtypes of the chemokine receptors. Development of the CXCR4 antagonists as effective drugs of HIV infection has been greatly hindered due to off-target side effects (Isberg et al, 2016).
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