Chemokine receptors, pivotal members of the GPCR superfamily, orchestrate immune cell trafficking, inflammatory modulation, and TME remodeling. Their dysregulated signaling is intimately linked to autoimmune diseases, infections, and cancer progression, positioning them as critical therapeutic targets. Recent breakthroughs in cryo-EM have unlocked high-resolution structures of these receptors, revealing molecular details of ligand engagement, activation dynamics, and disease-associated conformational states (Table 1).

Chemokine receptors leverage a conserved seven-transmembrane (TM1–7) helical bundle coupled with dynamic extracellular/intracellular loop (ECL/ICL) remodeling to achieve ligand specificity and signal transduction. Ligand binding follows a two-site recognition paradigm: the chemokine core engages the receptor N-terminus and ECLs via chemokine recognition site 1 (CRS1), while its N-terminal domain inserts into the TMD at CRS2, triggering activation. Structural studies of the CXCR4-CXCL12 complex illustrate this mechanism: CXCL12’s N-terminus penetrates the CRS2 pocket through salt bridges (D97/E288) and hydrophobic interactions, inducing a 10-Å TM6 outward shift to expose the G protein-binding interface. This conserved activation mechanism underpins receptor selectivity (e.g., CXCR4-CXCL12 exclusivity) and functional plasticity, enabling biased signaling toward G protein or β-arrestin pathways (Liu et al., 2024).

Chemokine receptor activation mechanisms rely critically on conformational dynamics within transmembrane helices and conserved functional motifs. For instance, CCR5 activation involves the toggle switch residues Y251^6.51 and W248^6.48, propagating structural changes through DRY, PIF, and NPxxY motifs to drive G protein coupling (Zhang et al., 2021). Structural studies of the CCR6/CCL20 complex reveal an atypical activation pathway: CCL20 binds superficially via a salt bridge with E198, inducing allosteric displacements in TM3, TM4, and TM6 without engaging classical toggle switch residues, illustrating mechanistic diversity in GPCR signaling (Wasilko et al., 2020). Constitutive activation phenomena, such as W86^2.60 conformational shifts in CCR5, demonstrate ligand-independent signaling through intrinsic helix dynamics, potentially contributing to chronic inflammation and autoimmune pathogenesis.

G protein coupling modes among chemokine receptors exhibit both conservation and divergence. In Gαi-coupled systems, CXCR2 utilizes its α5 helix to interact with TM3, TM5, TM6, ICL2, and ICL3, where hydrophobic residues (e.g., L353, L348) anchor into CXCR2’s hydrophobic pocket (Liu et al., 2020). Contrastingly, CCR5 employs ICL2 and ICL3 synergistically for Gαi engagement, with the α5 helix inserting into the intracellular region and stabilizing interactions through analogous hydrophobic contacts, while ICL3 assumes greater functional importance compared to CXCR2 (55). CX3CR1 displays distinct coupling architecture: minimal TM6 outward movement creates a constrained G protein-binding pocket, compensated by TM7 and H8 displacements. This receptor forms an extended interaction network involving TM1–TM7, ICL2, and ICL3, with a cholesterol-binding site stabilizing helix VI to modulate interface formation (Lu et al., 2022).

Structural elucidation of chemokine receptors has revolutionized our understanding of disease pathogenesis and therapeutic discovery. High-resolution structural studies clarified HIV-1’s co-receptor hijacking mechanism: viral gp120 structurally mimics chemokine engagement, with its V3 loop penetrating the CRS2 pocket through charge complementarity with receptor N-termini. Maraviroc sterically hinders gp120 binding by occupying the transmembrane allosteric pocket, unveiling precise inhibition mechanisms (Tan et al., 2013). The anti-CXCR4 antibody REGN7663 exemplifies structure-guided precision medicine, competing for extracellular binding via CDR-H3 loop interactions. In oncology, receptor oligomerization emerges as a novel therapeutic axis—cholesterol-stabilized CXCR4 tetramers constrain conformational flexibility to impair G protein coupling, proposing oligomeric state modulation for metastasis intervention (Saotome et al., 2025).

Collectively, chemokine receptor structural biology has decoded fundamental principles of ligand recognition, activation dynamics, and signal propagation while illuminating pathophysiological mechanisms in immunity, infection, and cancer. Integration of crystallography and cryo-EM captures receptor conformational landscapes across functional states, enabling rational design of allosteric modulators, biased agonists, and therapeutic antibodies. Future advances in receptor-complex structural determination coupled with AI-driven molecular engineering promise pathway-selective therapeutics targeting specific receptor subtypes, propelling innovation in treating inflammation, autoimmunity, and malignancies.

The “Two-Site Model” of chemokine-receptor interactions provides a structural paradigm for understanding ligand recognition and activation mechanisms (Figure 4). In this framework, chemokine binding occurs through two discrete sites that cooperatively induce receptor conformational changes and initiate downstream signaling.

CRS1 mediates initial high-affinity engagement through interactions between the chemokine’s globular core and the receptor’s N-terminus/ECLs. The chemokine core, stabilized by conserved disulfide bonds, adopts a compact tertiary structure whose N-loop and 40s-loop form polar and hydrophobic contacts with receptor residues. In the CCR2-CCL2 complex, CCL2’s N-loop and 40s-loop establish hydrogen bonds and salt bridges (e.g., Y49, D52) with CCR2’s N-terminus and ECL2, anchoring the primary binding interface while priming N-terminal insertion into the transmembrane pocket (Shao et al., 2022b). Similarly, CX3CL1’s globular core engages CX3CR1’s N-terminus and ECL2 via disulfide-mediated interactions (C28, C109), reinforcing CRS1 binding stability (Wasilko et al., 2020).

CRS2 involves N-terminal penetration of the chemokine into the receptor’s TMD, forming an orthosteric activation pocket. The chemokine’s N-terminus (5–10 residues) inserts into TMD helices, establishing polar and hydrophobic networks that trigger conformational rearrangements. In CCR8-CCL1 complexes, CCL1’s R24/K25 residues penetrate the TMD, forming hydrogen bonds and salt bridges with TM2/TM3/TM7 residues (Y113, D284) (Sun et al., 2023). XCL1’s K1/R2 similarly interact with XCR1’s TM3/TM5/TM7 (Y241, L245), stabilizing the active conformation and exposing the G protein-binding interface (Zhang et al., 2024).

The two-site model hinges on cooperative engagement of CRS1 and CRS2, where CRS1 primes structural transitions that enable chemokine N-terminal insertion into CRS2, triggering receptor activation. This stepwise mechanism ensures high-affinity ligand-receptor binding while enabling signaling specificity through precise conformational control. In the CCR6-CCL20 complex, CCL20’s globular core binds CCR6’s N-terminus and ECL2 via CRS1, while its N-terminus inserts into the TMD through CRS2, forming interactions with TM2/TM3/TM7 residues (E198, Y291). This dual-site architecture explains both ligand-receptor specificity and activation mechanics (Wasilko et al., 2020).

Beyond explaining binding affinity, the two-site model illuminates receptor activation principles and signal diversification mechanisms. By orchestrating conformational precision, chemokines gate specific downstream pathways, reflecting functional plasticity in ligand recognition. This framework also guides therapeutic design: maraviroc mimics chemokine binding to occupy CCR5’s CRS2, sterically blocking HIV gp120 engagement (Tan et al., 2013), while AMD3100 antagonizes CXCR4 by occluding CXCL12 binding at CRS2, inhibiting oncogenic signaling (Saotome et al., 2025).

Building on the two-site model, a more refined “three-step model” has been proposed: chemokines initially form a low-affinity, non-specific interaction with the receptor’s N-terminus through the N-loop/β3 region; subsequently, the N-terminus of the chemokine engages in a rate-limiting interaction with the receptor’s second binding site, achieving high-affinity and specific binding; finally, the receptor undergoes conformational rearrangement and activation (Sanchez et al., 2019). This model provides a more precise description of the complex binding and activation process between chemokines and their receptors.

In summary, the two-site model deciphers molecular logic underlying chemokine signaling and disease pathogenesis. Integrating structural and functional insights will accelerate targeted drug discovery, harnessing receptor dynamics for therapies against inflammation, infection, and cancer.

Autoimmune diseases (AIDs) are disorders driven by immune system dysregulation, where self-tolerance is breached, leading to pathogenic attack on host tissues (Basta et al., 2020). Central to this process, chemokine receptors orchestrate immune cell trafficking, directing leukocyte migration to sites of inflammation—a mechanism intricately linked to AID initiation and progression. Beyond migration, chemokines modulate immune cell activation, proliferation, and microenvironment remodeling, amplifying inflammatory cascades. Dysregulated chemokine-receptor axes frequently drive aberrant immune cell infiltration and tissue injury, as exemplified in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

SLE, a multisystem autoimmune disorder, manifests through autoantibody-mediated tissue damage influenced by genetic, environmental, and immune factors (Basta et al., 2020). Notably, chemokine-receptor networks are hyperactivated in SLE, particularly at inflammatory sites. In lupus nephritis (LN), CXCL13-CXCR5 signaling recruits B cells to kidneys, exacerbating renal inflammation, while CXCL9/10-CXCR3 axes drive T cell infiltration (Duan L. et al., 2024). Cutaneous lupus lesions exhibit CXCR3-mediated trafficking of memory/effector T cells via CXCL9-11, perpetuating skin damage. In SLE-associated cardiovascular complications, CXCR3⁺ T cell infiltration into arterial walls accelerates atherosclerosis. Neuropsychiatric SLE (NPSLE) involves CNS-targeted chemokines (e.g., CXCL8, CCL2, CXCL10) that facilitate monocyte and T cell migration, fostering neuroinflammation (Duan L. et al., 2024). Therapeutic targeting of chemokine pathways in SLE holds promise. CXCL13, CXCL12, and CCL2 blockade attenuates renal inflammation in preclinical models, while agents like bindarit show efficacy in early trials (Ble et al., 2011). However, functional redundancy within chemokine systems necessitates multiplex targeting strategies to overcome compensatory pathways.

RA, characterized by synovial hyperplasia and joint destruction, relies on chemokine-guided immune cell infiltration. Synovial T cell recruitment is mediated by CCR4, CCR5, CXCR3, CXCR4, and CXCR6, while CCR6 specifically directs Th17 cell migration (Murayama et al., 2023). B cell homing and germinal center formation depend on CXCL13-CXCR5 interactions, whereas CXCR1/2 orchestrate neutrophil influx via CXCL8. Beyond cell trafficking, chemokine receptors drive synovial angiogenesis (CXCL12-CXCR4) and bone erosion (CCR2/5-monocyte/macrophage axis) (Murayama et al., 2023). Multifunctional roles of these receptors underscore their potential as therapeutic nodes for halting RA progression.

HIV (Human Immunodeficiency Virus) subverts host immunity by selectively depleting CD4⁺ T cells, with chemokine receptors serving pivotal roles in viral entry. CXCR4 and CCR5 function as principal co-receptors for T-tropic and macrophage-tropic HIV-1 strains, respectively. During early infection, CCR5-dependent viral entry into macrophages and resting T cells correlates with indolent disease progression. Virological evolution toward CXCR4 tropism enables activated T cell infection, driving rapid CD4⁺ depletion and clinical deterioration (Kalinkovich et al., 1999).

The CCR5Δ32 mutation confers natural resistance to HIV-1, inspiring therapeutic CCR5 antagonists like maraviroc for clinical use (Venuti et al., 2017). CXCR4-targeted strategies face translational challenges due to its essential physiological roles in hematopoiesis and immunity. While CXCR4 inhibitors (e.g., AMD3100) mobilize hematopoietic stem cells (Huang et al., 2021), systemic blockade risks disrupting homeostatic functions. Precision targeting of CXCR4-HIV interactions may emerge through mechanism-based drug design, expanding therapeutic options.

Chemokine receptors orchestrate immune cell dynamics across inflammation stages. CXCR2 directs neutrophil chemotaxis via IL-8/CXCL8 sensing, establishing frontline antimicrobial defense. Concurrently, CCR2-CCL2 signaling mobilizes monocytes from bone marrow to inflamed tissues, differentiating into macrophages/DCs for pathogen clearance and tissue remodeling.

Inflammatory resolution involves chemokine receptor-mediated immune cell reprogramming. CCR7 upregulation licenses antigen-laden DCs to migrate toward lymphoid CCL19/CCL21 gradients, bridging innate and adaptive immunity through T cell priming. This spatiotemporal regulation enhances antigen-specific responses while preventing immunopathology.

Chemokine receptors operate within dynamic signaling networks: CXCR4/CCR5 coregulate immune recruitment, with expression levels mirroring inflammatory phase transitions. Receptor homo-/heterodimerization further amplifies chemosensitivity, enabling nuanced immune regulation within complex microenvironments (Chen et al., 2018).

Chemokine receptors critically regulate TME dynamics by mediating crosstalk between immune and tumor cells, driving tumor progression, metastasis, and immune evasion. The CXCR4-CXCL12 axis is pivotal for tumor cell migration and pre-metastatic niche formation in bone marrow and lymph nodes, while chemokine receptor-mediated recruitment of TAMs and MDSCs establishes an immunosuppressive microenvironment that subverts immune surveillance (Bian et al., 2019).

These receptors orchestrate immune cell trafficking from the vasculature into tumors and spatially organize their distribution, enabling functional interactions with stromal and malignant cells. CXCR3, via ligands CXCL9/10/11, enhances CD8⁺ T cell and NK cell infiltration and synergizes with antigen-presenting cells to amplify antitumor immunity. CXCR6-CXCL16 signaling sustains effector T cell survival in perivascular niches through crosstalk with CXCL16⁺ dendritic cells, whereas CCR4/CCR8 facilitate T_reg accumulation to suppress immune responses (Mempel et al., 2024). Dysregulated chemokine receptor activity is intimately linked to immune checkpoint blockade (ICB) resistance. CCR4-dependent T_reg infiltration represents a central resistance mechanism, positioning CCR4 antagonists and CXCR4 inhibitors as strategic tools to remodel the TME and restore immunotherapy efficacy. CXCR4 inhibitors block metastasis through multiple mechanisms, including competitive inhibition of CXCL12 binding, prevention of G protein activation, and promotion of receptor internalization. By disrupting ligand-induced CXCR4 signaling, these inhibitors impede downstream pathways involved in cytoskeletal remodeling, adhesion, and migration, thereby limiting tumor cell dissemination and metastatic colonization. Additionally, CXCR4 blockade modulates immune cell positioning within the tumor microenvironment, enhancing immune infiltration and improving responses to immunotherapy (Yi et al., 2024).

Chemokine receptors enable tumor immune escape through multifaceted mechanisms. The CXCL12-CXCR4 axis recruits T_regs and MDSCs to inhibit cytotoxic T/NK cell function, while hypoxia and acidosis downregulate CXCR3/CCR5 on NK cells, impairing their migration. Tumor-derived TGF-β suppresses chemokine receptor expression, limiting immune cell infiltration. Concurrently, CCL22-CCR4 and CCL2-CCR2 axes drive immunosuppression via T_reg/MDSC/TAM recruitment, and CXCL8-CXCR1/2 signaling recruits granulocytic MDSCs/neutrophils to promote angiogenesis and immune suppression. Furthermore, CXCL12-CXCR4 induces regulatory CD8⁺ T cells that inhibit tumor-specific effector T cell activation, culminating in immune escape (Ran et al., 2022).

Chemokine receptors exhibit dualistic roles in neurological pathologies, balancing neuroprotection and exacerbation of damage. CX3CR1 orchestrates microglial dynamics in the CNS, regulating inflammatory tone and synaptic refinement. During neurodevelopment, CX3CR1 guides microglial brain infiltration, maintaining homeostasis and suppressing inflammation to support memory and learning. While CX3CR1 restrains excessive microglial activation under steady-state conditions, it licenses reactive gliosis during inflammation, exhibiting context-dependent neuroprotection or injury (Sheridan and Murphy, 2013). CX3CR1 upregulation in neuroinflammation models fuels pathogenic crosstalk between activated glia and neurons, amplifying inflammatory cascades (Xu et al., 2016).

In neurodegenerative pathologies such as Parkinson’s (PD) and Alzheimer’s (AD) diseases, CX3CR1 modulates microglial responses to neuronal injury. PD models reveal that CX3CR1 loss impairs microglial damage sensing, escalating neuroinflammation. Normally, CX3CR1-CX3CL1 signaling dampens microglial hyperactivation to preserve neural homeostasis; CX3CR1 deficiency, however, compromises debris clearance, worsening neuronal loss and inflammatory escalation. Conversely, CX3CR1 overexpression triggers microglial overactivation and pro-inflammatory mediator release, disrupting synaptic integrity and neuronal transmission (Subbarayan et al., 2022). In AD models, microglial CX3CR1 ablation mitigates neuronal degeneration, highlighting its disease-stage-specific duality (Fuhrmann et al., 2010).

Chemokine receptors play central roles in various pathophysiological processes, including inflammation, immune cell migration, tumor microenvironment remodeling, and viral entry. The interaction between chemokines and their receptors exhibits a pronounced ligand–receptor promiscuity, where a single chemokine can activate multiple receptors, and conversely, a single receptor can be triggered by multiple chemokines. As a result, the development of highly selective ligands at the molecular level remains a major challenge in chemokine-targeted drug discovery. Systematic sequence alignment provides a crucial theoretical basis for understanding the conserved and variable features among chemokine receptor subtypes, thereby informing rational design of selective therapeutics (Supplementary Figure S1).

First, the transmembrane helices (TM1–TM7) of chemokine receptors display a high degree of conservation across receptor families, particularly with respect to structurally and functionally critical motifs. These include the DRY (Asp-Arg-Tyr) motif in TM3, the CWxP motif in TM6, and the NPxxY motif in TM7. These conserved sequences are essential for G protein coupling, conformational changes, and activation, thereby maintaining core signaling functions of GPCRs. The alignment reveals that these motifs are ubiquitously conserved across the CCR, CXCR, XCR, and CX3CR families. Their conservation implies that small-molecule ligands targeting these motifs are likely to interact with multiple receptor subtypes, increasing the risk of off-target effects. Therefore, such regions are more appropriate as structural scaffolds to retain functional integrity rather than as primary targets for pharmacological intervention.

In contrast, the extracellular regions—particularly the second extracellular loop (ECL2) and the N-terminal domain—exhibit substantial sequence variability among different receptors. These domains are directly involved in ligand recognition and binding, and critically influence receptor specificity and affinity. For example, while CCR5, CCR2, and CX3CR1 share similar transmembrane architecture, alignment reveals marked differences in their ECL2 and N-terminal sequences in terms of amino acid length, polarity, charge distribution, and potential glycosylation sites. These differences contribute to distinct ligand-binding microenvironments, which underlie the selective activity of chemokine receptor-targeted agents such as the CCR5 antagonist Maraviroc. Sequence alignment thus helps to identify “selectivity-determining residues,” which serve as precise molecular targets for SBDD.

Moreover, sequence comparison facilitates the identification of receptor subtype-specific structural features, which can guide the development of covalent inhibitors, allosteric modulators, or monoclonal antibody therapeutics. For instance, compared with other CXCR receptors, CX3CR1 contains several non-conserved residues within the TM5–TM7 region, which may form unique hydrophobic or cryptic binding pockets amenable to selective targeting. Similarly, atypical chemokine receptors (ACKR1–ACKR5), although structurally classified as GPCRs, contain mutations at canonical G protein coupling motifs, rendering them incapable of signal transduction via traditional G protein pathways. These features, readily identifiable through sequence alignment, suggest new avenues for developing “decoy” or “scavenger” therapeutic strategies that modulate chemokine availability rather than downstream signaling.

Finally, when combined with structural prediction techniques, sequence alignment serves as a foundation for homology modeling or machine learning-based 3D structure prediction (e.g., AlphaFold3) (Abramson et al., 2024). This allows detailed analysis of how non-conserved residues impact the spatial conformation of receptor–ligand complexes. Computational chemistry methods can further validate whether these residues contribute to ligand binding affinity, specificity, or induced conformational transitions, thereby directly linking sequence variation to functional divergence. Such integration of sequence and structural data offers a powerful framework for guiding the rational design of highly selective chemokine receptor modulators.

SBDD targeting GPCRs has evolved from traditional reliance on X-ray crystallography and nuclear magnetic resonance (NMR) to leverage cryo-EM and computational breakthroughs, revolutionizing therapeutic discovery. Historically, X-ray/NMR-derived structures of orthosteric sites enabled rational ligand design through molecular docking and virtual screening, optimizing compound affinity and selectivity. However, these methods struggled to resolve dynamic receptor conformations and explore allosteric sites, limiting mechanistic insights. Recent advances in cryo-EM now capture GPCRs in near-atomic resolution across functional states—particularly when complexed with G proteins or β-arrestin—unlocking structural blueprints for designing allosteric modulators and biased ligands. Concurrently, large-scale virtual screening accelerates hit identification, expanding the druggable GPCR landscape (Congreve et al., 2020).

Modern GPCR drug discovery integrates cryo-EM-derived structures with computational chemistry to drive precision. SBDD resolves ligand-bound receptor complexes (agonists, antagonists, allosteric modulators), mapping critical binding motifs to guide virtual screening and molecular docking. This structure-informed approach identifies novel chemotypes and optimizes existing scaffolds for enhanced affinity/selectivity prior to experimental validation. Compared to traditional methods, SBDD’s atomic-level insights enable pharmacophore refinement, accelerated fragment-based design, and biased agonist engineering to minimize off-target effects. By reducing screening randomness and streamlining lead optimization, SBDD shortens development timelines and lowers costs, transforming GPCR drug discovery (Duan J. et al., 2024) (Figure 5).

Structural insights into GPCRs have catalyzed precision drug discovery. Analysis of Adenosine A2A Receptor (A2AR) uncovered an underexplored hydrophobic subpocket, enabling the design of AZD4635—a highly selective antagonist with immuno-oncology potential (Marshall and Djamgoz, 2018). Fragment-based drug design (FBDD) synergized with X-ray data accelerates lead optimization, exemplified by HTL0014242, a negative allosteric modulator targeting Metabotropic Glutamate Receptor 5 (mGlu5) (Christopher et al., 2015). To address GPCR polymorphism and dynamics, mini-G proteins and nanobodies stabilize active receptor conformations, facilitating structural resolution of GPCR-G protein/β-arrestin complexes and elucidating signaling mechanisms.

Recent GPCR drug development advances highlight novel therapeutic paradigms. Allosteric modulators, binding non-orthosteric sites, fine-tune signaling with enhanced selectivity, as demonstrated by Metabotropic Glutamate Receptor (mGluR) and Muscarinic Acetylcholine Receptor M4 (M4 mAChR) modulators in neuropsychiatric trials (Orgován et al., 2019). Biased ligands decouple downstream pathways: oliceridine, a μ-opioid receptor agonist, retains analgesia while mitigating respiratory depression via selective G protein activation (Kenakin, 2019). Biologics like monoclonal antibodies/nanobodies expand GPCR targeting, with Glucagon-Like Peptide-1 (GLP-1) agonist/Gastric Inhibitory Polypeptide (GIP) antagonist combos showing efficacy against obesity/diabetes (Gutgesell et al., 2024). Drug repurposing strategies leverage existing pharmacotherapies: the β-blocker propranolol now treats infantile hemangiomas (Léauté-Labrèze et al., 2008) and cancer (Lin et al., 2023), shortening development timelines and de-risking translation (Lorente et al., 2025).

Targeting chemokine receptors represents a frontier in biomedical research, offering transformative therapeutic opportunities alongside persistent challenges. Advances in cryo-EM have decrypted high-resolution architectures of chemokine receptor complexes, unlocking ligand-binding architectures and critical residue networks. These insights provide critical molecular insights for small-molecule optimization and high-throughput drug screening. Allosteric antagonists, emerging as a strategic focus, surpass traditional orthosteric inhibitors by modulating receptor conformations, enhancing selectivity, and enabling biased signaling regulation—overcoming limitations in treating inflammation, cancer, and immune dysregulation.

The CCR5 structural paradigm has redefined anti-HIV drug design. Cryo-EM maps of CCR5 reveal its ligand-binding pocket topology, guiding the development of maraviroc, an allosteric inhibitor that occupies a deep TMD cavity formed by TM1–3, TM5–7. Maraviroc anchors via hydrogen bonds (E283, Y251) and hydrophobic contacts (Y108, F109, W248), stabilizing CCR5’s inactive state to block HIV-1 entry (Tan et al., 2013). Comparative structural analyses highlight divergent ligand-binding mechanisms between CCR5 and CXCR4. While both receptors share global folds, CCR5’s more accessible pocket and distinct charge distribution contrast with CXCR4’s N-terminus/ECL2-shielded cavity and acidic N-terminal residues, aligning with HIV-1 V3 loop tropism. These differences rationalize co-receptor specificity and inform allosteric inhibition strategies (Figure 6).

Extending these principles, CCR9’s structural resolution uncovers an intracellular allosteric site. Vercirnon engages this pocket by interacting with TM1–3, TM6–7, and H8, locking CCR9 in a G protein-uncoupled state. This intracellular antagonism mechanism diverges from classical GPCR ligand binding modes, broadening therapeutic design paradigms (Oswald et al., 2016).

Collectively, chemokine receptor structural biology delivers molecular blueprints for precision drug design, illuminating ligand engagement logic and accelerating therapies for HIV, immune disorders, and beyond (Table 2).