Human CXCR1 blocking peptide

Background: Genetic variations of Toll like receptor 4 (TLR4) and CXC-chemokine receptor typel (CXCR1), the key elements of innate immune system and their association with urinary tract infection (UTI) were studied in general population. In present study we investigate genetic variation of these genes in diabetic patients (3 to 4 times higher prevalence of UTI in comparison to general population). Methods: A total 1100 subjects (318 diabetic patients with UTI, 324 diabetic patients without UTI, 200 non diabetic UTI patients and 260 age matched healthy control) were enrolled in the study. SNPs of TLR4 rs4986790, rs4986791 and CXCR1 rs2234671 was assessed by PCR-RFLP and PCR-SSP respectively. Results: Statistical analysis revealed that A/G genotype and G allele of TLR4 rs4986790 are significantly associated with UTI in both diabetics and nondiabetic patients in comparison to healthy control. Similarly CT genotype and T allele of TLR4 rs4986791 are also significantly associated with UTI in both groups. We also found that prevalence of A/G genotype of TLR4 rs4986790 and CT genotype of TLR4 rs4986791 are significantly higher in patients of diabetes with UTI in comparison to diabetic patients without UTI. We did not find any association of CXCR1 rs2234671 polymorphism with UTI by comparing with any group. Conclusion: We found that TLR4 rs4986790 and rs4986791 gene polymorphism is a risk for UTI development in both diabetic and nondiabetic patients in north Indian population.

Tyrosine sulfation, a post-translational modification found on many chemokine receptors, typically increases receptor affinity for the chemokine ligand. A previous bioinformatics analysis suggested that a sulfotyrosine (sY)-binding site on the surface of the chemokine CXCL12 may be conserved throughout the chemokine family. However, the extent to which receptor tyrosine sulfation contributes to chemokine binding has been examined in only a few instances. Computational solvent mapping correctly identified the conserved sulfotyrosine-binding sites on CXCL12 and CCL21 detected by nuclear magnetic resonance (NMR) spectroscopy, demonstrating its utility for hot spot analysis in the chemokine family. In this study, we analyzed five chemokines that bind to CXCR2, a subset of which also bind to CXCR1, to identify hot spots that could participate in receptor binding. A cleft containing the predicted sulfotyrosine-binding pocket was identified as a principal hot spot for ligand binding on the structures of CXCL1, CXCL2, CXCL7, and CXCL8, but not CXCL5. Sulfotyrosine titrations monitored via NMR spectroscopy showed specific binding to CXCL8, but not to CXCL5, which is consistent with the predictions from the computational solvent mapping. The lack of CXCL5-sulfotyrosine interaction and the presence of CXCL8-sulfotyrosine binding suggests a role for receptor post-translational modifications regulating ligand selectivity.