Structural basis of the interactions between CXCR4 and CXCL12/SDF-1 revealed by theoretical approaches
Lei Xu1, Youyong Li, Huiyong Sun
1Institute of Functional Nano & Soft Materials FUNSOM and Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu 215123, China.
Abstract:
The G protein-coupled chemokine receptor CXCR4 is implicated in a variety of physiological responses that also share several downstream effectors involved in multiple pathological processes. The interaction between CXCR4 and its natural ligand CXCL12/stromal-derived factor-1 (SDF-1) plays important roles in cancer metastasis, HIV-1 infection, and inflammatory diseases. Therefore, investigating the CXCR4-CXCL12 interaction is critical for understanding the molecular mechanisms of the modulation of chemokine-receptor functions and designing new pharmaceutical agents to target the CXCR4-CXCL12 pathway. Based on known experimental data, the interaction between CXCR4 and CXCL12 was predicted by an integrated protocol, which combines protein-protein docking, molecular dynamics (MD) simulations, Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding free energy calculations, and MM/GBSA binding free energy decomposition analysis. The predicted CXCR4-CXCL12 binding pattern is in good agreement with the experimental data. Analysis of the binding structure reveals an obvious electrostatic complementarity between CXCR4 and CXCL12. Moreover, significant conformational rearrangements were observed during the 50 ns MD simulations. In particular, the basic Lys1 at the CXCL12 N-terminus, an essential residue in receptor activation, forms a strong polar interaction with the Glu32 in the CXCR4 extracellular region. It facilitates the significant movement of TM5 and TM6 in the conformational transition, which is coupled to the association with the intracellular signal transduction pathways via heterotrimer G-protein. Based on the dynamic and energetic analyses, a two-site binding model was proposed. We believe that our study provides useful information for understanding the mechanisms of CXCR4 ligand binding and structure-based drug design of CXCR4.
Insights
The G protein-coupled receptor CXCR4 and its ligand CXCL12 interaction is crucial for cancer and HIV. This study models their binding, revealing key interactions for drug design targeting this pathway.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- The G protein-coupled chemokine receptor CXCR4 and its ligand CXCL12 are involved in cancer metastasis, HIV-1 infection, and inflammatory diseases.
- Understanding the CXCR4-CXCL12 interaction is vital for developing targeted pharmaceutical agents.
Purpose of the Study:
- To predict and analyze the binding interaction between CXCR4 and CXCL12.
- To provide insights into the molecular mechanisms of chemokine-receptor function modulation.
- To support structure-based drug design for targeting the CXCR4-CXCL12 pathway.
Main Methods:
- Integrated computational protocol combining protein-protein docking, molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations.
- Analysis of binding free energy decomposition.
- 50 ns MD simulations to observe conformational changes.
Main Results:
- The predicted CXCR4-CXCL12 binding pattern aligns well with experimental data.
- Strong electrostatic complementarity was observed between CXCR4 and CXCL12.
- Key interactions, including Lys1 (CXCL12) with Glu32 (CXCR4), were identified, driving conformational changes and G-protein signaling.
- A two-site binding model was proposed based on dynamic and energetic analyses.
Conclusions:
- The study provides a detailed molecular understanding of the CXCR4-CXCL12 binding mechanism.
- The findings offer valuable information for structure-based drug design targeting CXCR4.
- The proposed two-site binding model enhances comprehension of chemokine receptor-ligand interactions.
