Mechanism of Peptide Agonist Binding in CXCR4 Chemokine Receptor

Pawnikar, Shristi; Miao, Yinglong

doi:10.3389/fmolb.2022.821055

Title: Mechanism of Peptide Agonist Binding in CXCR4 Chemokine Receptor

Journal Article · Fri Mar 11 00:00:00 EST 2022 · Frontiers in Molecular Biosciences

DOI:https://doi.org/10.3389/fmolb.2022.821055· OSTI ID:1983093

Pawnikar, Shristi ^[1]; Miao, Yinglong ^[1]

Univ. of Kansas, Lawrence, KS (United States)

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.

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Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC); National Institutes of Health (NIH); National Science Foundation (NSF)

Grant/Contract Number:: AC02-05CH11231; R01GM132572; ACI-1548562

OSTI ID:: 1983093

Journal Information:: Frontiers in Molecular Biosciences, Vol. 9; ISSN 2296-889X

Publisher:: Frontiers Media S.A.Copyright Statement

Country of Publication:: United States

Language:: English

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Title: Mechanism of Peptide Agonist Binding in CXCR4 Chemokine Receptor

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