Distinct Functional Sites for Human Immunodeficiency Virus Type 1 and Stromal Cell-Derived Factor 1α on CXCR4 Transmembrane Helical Domains

Tian, Shaomin; Choi, Won Tak; Liu, Dongxiang; Pesavento, James J.; Wang, Youli; An, Jing; Sodroski, Joseph; Huang, Ziwei

doi:10.1128/jvi.79.20.12667-12673.2005

Cited by 72 publications

(153 citation statements)

References 36 publications

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“…Note that we have tested various strains of gp120, including both X4-and R5-preferring gp120, and found that many of them caused neurotoxicity in RCCs. 3 Although the possibility remains that these CXCR4-specific SMM-chemokines could activate other known or unknown signaling pathways, the importance of steric hindrance in their neuroprotective mechanism is further supported by our mutational analysis of their binding sites, which shows overlap in the CXCR4 binding residues of these SMM-chemokines with X4-preferring gp120 but not with SDF-1␣ (48,49). Another mechanism whereby CCR5-selective ligands could suppress the neuroprotective action of these new CXCR4 antagonists would be heterologous desensitization (50,51), but such an effect need not be invoked here because the CCR5 ligands RCP188, RCP189, and gp120 BAL are neurotoxic on their own.…”

Section: Mechanism(s) By Which Antagonist Ccr5-selective Smm-mentioning

confidence: 69%

Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

Choi¹,

Kaul

Kumar³

et al. 2007

Journal of Biological Chemistry

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As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1␣ or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1␣ or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120 IIIB , and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival.

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Section: Mechanism(s) By Which Antagonist Ccr5-selective Smm-mentioning

confidence: 69%

Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

Choi¹,

Kaul

Kumar³

et al. 2007

Journal of Biological Chemistry

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“…One of these CXCR4 residues, W94 2.60 , is highly conserved among chemokine receptors, has been implicated in binding the small molecule antagonist IT1t and vMIP-II (8,9), and the equivalent residue in the chemokine receptor CCR5 (W86 2.60 ) has also been shown to play a role in ligand binding (24). Additional signal initiator residues identified in our screen include Y45 1.39 , Y116 3.32 , and E288 7.39 , all previously reported as binding and/ or signaling determinants in CXCR4 (13,19,22,25). In the CXCR4:CXCL12 complex model, each of these four residues directly contacts or is in close proximity to the distal N terminus of CXCL12 (residues K1 and P2), which is widely recognized as the critical domain of the chemokine that initiates signaling (16,26).…”

Section: Significancementioning

confidence: 90%

“…Three of these critical residues are buried directly below the CXCR4 signal initiator residues discussed above. These residues are F292 7.43 , which has been previously shown to be important for CXCR4 activity (17,19), A291 7.42 , which has a known role in introducing constitutive activity in CCR5 (27), and W252 6.48 , which is part of the well-characterized CWxP rotamer motif (28,29). Homologous positions in the A2AR structure (H278 7.43 and S277 7.42 ) have been shown to move closer to helix III upon agonist binding (30), supporting an important role for these residues in GPCR signal transmission.…”

Section: Significancementioning

confidence: 99%

“…CXCR4 residues involved in chemokine engagement. The interaction of CXCL12 with CXCR4 is known to be mediated by two distinct epitopes (1,8,12,(16)(17)(18)(19)(20)(21)(22). In the first [chemokine recognition site 1 (CRS1)], the unstructured N terminus of CXCR4 interacts with the globular core of the chemokine, specifically with the N loop and the 40s loop of CXCL12.…”

Section: Significancementioning

confidence: 99%

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Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices

Wescott

Kufareva

Paes

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

103

183

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The atomic-level mechanisms by which G protein-coupled receptors (GPCRs) transmit extracellular ligand binding events through their transmembrane helices to activate intracellular G proteins remain unclear. Using a comprehensive library of mutations covering all 352 residues of the GPCR CXC chemokine receptor 4 (CXCR4), we identified 41 amino acids that are required for signaling induced by the chemokine ligand CXCL12 (stromal cell-derived factor 1). CXCR4 variants with each of these mutations do not signal properly but remain folded, based on receptor surface trafficking, reactivity to conformationally sensitive monoclonal antibodies, and ligand binding. When visualized on the structure of CXCR4, the majority of these residues form a continuous intramolecular signaling chain through the transmembrane helices; this chain connects chemokine binding residues on the extracellular side of CXCR4 to G proteincoupling residues on its intracellular side. Integrated into a cohesive model of signal transmission, these CXCR4 residues cluster into five functional groups that mediate (i) chemokine engagement, (ii) signal initiation, (iii) signal propagation, (iv) microswitch activation, and (v) G protein coupling. Propagation of the signal passes through a "hydrophobic bridge" on helix VI that coordinates with nearly every known GPCR signaling motif. Our results agree with known conserved mechanisms of GPCR activation and significantly expand on understanding the structural principles of CXCR4 signaling.T he CXC chemokine receptor 4 (CXCR4) belongs to the G protein-coupled receptor (GPCR) superfamily of proteins, the largest class of integral membrane proteins encoded in the human genome, comprising greater than 30% of current drug targets. Deregulation of CXCR4 expression in multiple human cancers, its role in hematopoietic stem cell migration, and the utilization of CXCR4 by HIV-1 for T-cell entry, make this receptor an increasingly important therapeutic target (1). One FDA-approved drug against CXCR4 is currently on the market (Mozobil, for hematopoietic stem cell mobilization), and multiple additional drugs against this target are in development for oncology and other indications (2).The crystal structures of class A GPCR superfamily members in their active and inactive conformations (reviewed in refs. 3 and 4) provide unprecedented insight into the structural basis of ligand binding, G protein coupling, and activation of GPCRs via rearrangements of transmembrane (TM) helices. GPCR helices V and VI in particular, and in some cases III and VII, are known to undergo significant conformational changes upon activation (5-7). However, static images alone have not been able to explain the residue-level mechanisms underlying the dynamic helical shifts that mediate GPCR signal transduction. Additionally, only inactive state structures have been solved for CXCR4 and most other GPCRs (8,9). Over the last two decades, extensive mutagenesis studies of GPCRs in general [collectively describing >8,000 mutations (gpcrdb.org)] and of CX...

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“…In line with the findings in the present study, the D97A, D187A, and E288A mutations have previously been found to affect both the binding and signaling of CXCL12. 37,[45][46][47][48][49] Moreover, Trp 94 and Tyr 116 , together with the three aforementioned residues, have been implicated as part of "site two" in the "two-site model" for binding of CXCL12 to CXCR4. 33,45,50,51 Additionally, the direct interaction of Tyr 116 with agonists has been suggested in activation of GPCRs.…”

Section: Resultsmentioning

confidence: 99%

Probing the Molecular Interactions between CXC Chemokine Receptor 4 (CXCR4) and an Arginine-Based Tripeptidomimetic Antagonist (KRH-1636)

et al. 2015

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Abstract:We here report an experimentally verified binding mode for the known tripeptidomimetic CXCR4 antagonist KRH-1636 (1). A limited SAR study was first conducted based on the three functionalities of 1, followed by site-directed mutagenesis studies. The receptor mapping showed that both the potency and affinity of 1 were dependent on the transmembrane residues His 113 , Asp 171 , Asp 262 , and His 281 , and also suggested the involvement of

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Distinct Functional Sites for Human Immunodeficiency Virus Type 1 and Stromal Cell-Derived Factor 1α on CXCR4 Transmembrane Helical Domains

Cited by 72 publications

References 36 publications

Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

Signal transmission through the CXC chemokine receptor 4 (CXCR4) transmembrane helices

Probing the Molecular Interactions between CXC Chemokine Receptor 4 (CXCR4) and an Arginine-Based Tripeptidomimetic Antagonist (KRH-1636)

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