(69d) Elucidating Two Anti-HIV-1 and Cancer-Associated Structures: CXCL12 (SDF-1α) Binding to CXCR4 and CCL5 (Rantes) Binding to CCR5

The chemotactic signaling induced by the binding of chemokines CXCL12 (SDF-1α) and CCL5 (RANTES) to chemokine receptors CXCR4[1] and CCR5 [2], respectively, is of significant biological importance. Chemokines CXCL12 and CCL5 constitute potential therapeutic axes for HIV-1, as their binding to chemokine receptors [1,2] blocks the HIV-1 gp120 V3 loop binding to CXCR4 [3] and CCR5 [4], respectively. In addition, several studies provided growing evidence for the involvement of the CXCL12 : CXCR4 and CCL5 : CCR5 axes in a series of malignancies, including breast, prostate, colorectal cancers[1,2]. Therefore, the elucidation of the CXCL12 : CXCR4 and CCL5 : CCR5 complex structures is of utmost medical importance for the design of novel therapeutic compounds which can block either the cancer-associated chemokine binding-signaling or the HIV-1 binding to chemokine receptors CXCR4 and CCR5.

We developed a computational protocol which is predominantly based on free energy calculations and molecular dynamics simulations, to obtain insights into the molecular recognition of CXCR4 by CXCL12 [1] and CCR5 by CCL5 [2]. We report, what is to our knowledge, the first computationally derived CXCL12 : CXCR4 [1] and CCL5 : CCR5 [2] complex structures which are in excellent agreement with experimental findings and clarify the functional role of CXCL12 / CCL5 and CXCR4 / CCR5 residues which are associated with binding and signaling [1,2]. An abundance of polar and non-polar interactions contribute to the tight binding observed in both CXCL12 : CXCR4 and CCL5 : CCR5 complex structures[1,2]. A similar computational protocol was also applied to delineate the binding of a dual tropic HIV-1 gp120 V3 loop in complex with CXCR4 [3] and CCR5 [4]; a dual tropic HIV-1 gp120 V3 loop recognizes both chemokine receptors CXCR4 and CCR5. A comparison between the (i) CXCL12 / CCL5 binding to CXCR4 / CCR5 [1,2] and (ii) the dual tropic HIV-1 gp120 V3 loop binding to CXCR4 / CCR5 [3,4] shows that both the chemokines [1,2] and the HIV-1 gp120 V3 loop [3,4]share the same binding pockets of the chemokine receptors. Thus, our work provides insights into the blocking mechanism of HIV-1 by chemokines.

References

1. Tamamis P, Floudas CA (2014) Elucidating a Key Component of Cancer Metastasis: CXCL12 (SDF-1α) Binding to CXCR4. J Chem Inf Model 54 (4): 1174-1188.

2. Tamamis P, Floudas CA (2014) Elucidating a Key Anti-HIV-1 and Cancer-Associated Axis: CCL5 (Rantes) Binding to CCR5. Paper Under Review.

3. Tamamis P, Floudas CA (2013) Molecular recognition of CXCR4 by a dual tropic HIV-1 gp120 V3 loop. Biophys J 105 (6): 1502–1514.

4. Tamamis P, Floudas CA (2014) Molecular recognition of CCR5 by an HIV-1 gp120 V3 loop. PLoS ONE 9 (4): e95767.