Diverging Mechanisms of Activation of Chemokine Receptors Revealed by Novel Chemokine Agonists

CXCL8/interleukin-8 is a pro-inflammatory chemokine that triggers pleiotropic responses, including inflammation, angiogenesis, wound healing and tumorigenesis. We engineered the first selective CXCR1 agonists on the basis of residue substitutions in the conserved ELR triad and CXC motif of CXCL8. Our data reveal that the molecular mechanisms of activation of CXCR1 and CXCR2 are distinct: the N-loop of CXCL8 is the major determinant for CXCR1 activation, whereas the N-terminus of CXCL8 (ELR and CXC) is essential for CXCR2 activation. We also found that activation of CXCR1 cross-desensitized CXCR2 responses in human neutrophils co-expressing both receptors, indicating that these novel CXCR1 agonists represent a new class of anti-inflammatory agents. Further, these selective CXCR1 agonists will aid at elucidating the functional significance of CXCR1 in vivo under pathophysiological conditions

An interaction network in the polymerase active site is a prerequisite for Watson-Crick base pairing in pol g

Pol gamma is essential for mitochondrial genome integrity. Mutations to the polymerase causes disruption to it's various functions. Mutations in the 853 site causes various neurological issues. Structural and computational analysis of the wild-type and the mutants show that the mutation inhibits the process of opening and closing of the polymerase necessary for nucleotide incorporation. Furthermore, the dNTP does not form Watson-Crick base pairing with the templating residue, which is necessary for the reaction to take place