Structure/function of human herpesvirus-8 MIP-II (1-71) and the antagonist N-terminal segment (1-10).
Kaposi's sarcoma-associated herpesvirus encodes a chemokine called vMIP-II that has been shown to be a broad range human chemokine receptor antagonist. Two N-terminal peptides, vMIP-II(1-10) and vMIP-II(1-11)dimer (dimerised through Cys11) were synthesised. Both peptides are shown to bind the CXC chemokine receptor 4 (CXCR4). vMIP-II(1-10) was 1400-fold less potent than the native protein whilst the vMIP-II(1-11)dimer was only 180-fold less potent. In addition, both peptides are CXCR4 antagonists. Through analysis of non-standard, long mixing time two-dimensional nuclear Overhauser enhancement spectroscopy experiments, 13C relaxation data and amide chemical shift temperature gradients for the N-terminus of vMIP-II, we show that this region populates a turn-like structure over residues 5-8, both in the presence and absence of the full protein scaffold. This major conformation is likely to be in fast exchange with other conformational states but it has not previously been detected in monomeric chemokine structures. This and other studies [Elisseeva et al. (2000) J. Biol. Chem. 275, 26799-26805] suggest that there may be a link between the structuring of the short N-terminal chemokine peptides and their ability to bind their receptor.
Crump
M P
MP
Protein Engineering Network of Centers of Excellence, Department of Biochemistry, Heritage Medical Research Center, University of Alberta, Edmonton, Canada.
Elisseeva
E
E
Gong
J
J
Clark-Lewis
I
I
Sykes
B D
BD
D001665:Binding Sites; D001667:Binding, Competitive / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D054377:Chemokine CXCL12; D018925:Chemokines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D019743:Chemokines, CXC / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011487:Protein Conformation; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; D010446:Peptide Fragments; D019718:Receptors, CXCR4; C108059:vMIP-II