Solution structure and basis for functional activity of stromal cell-derived factor-1; dissociation of CXCR4 activation from binding and inhibition of HIV-1.
The three-dimensional structure of stromal cell-derived factor-1 (SDF-1) was determined by NMR spectroscopy. SDF-1 is a monomer with a disordered N-terminal region (residues 1-8), and differs from other chemokines in the packing of the hydrophobic core and surface charge distribution. Results with analogs showed that the N-terminal eight residues formed an important receptor binding site; however, only Lys-1 and Pro-2 were directly involved in receptor activation. Modification to Lys-1 and/or Pro-2 resulted in loss of activity, but generated potent SDF-1 antagonists. Residues 12-17 of the loop region, which we term the RFFESH motif, unlike the N-terminal region, were well defined in the SDF-1 structure. The RFFESH formed a receptor binding site, which we propose to be an important initial docking site of SDF-1 with its receptor. The ability of the SDF-1 analogs to block HIV-1 entry via CXCR4, which is a HIV-1 coreceptor for the virus in addition to being the receptor for SDF-1, correlated with their affinity for CXCR4. Activation of the receptor is not required for HIV-1 inhibition.
Crump
M P
MP
Protein Engineering Network of Centers of Excellence (PENCE) and Department of Biochemistry, 713 Heritage Medical Research Center, University of Alberta, Edmonton, Alberta, Canada T6G 2S2.
Gong
J H
JH
Loetscher
P
P
Rajarathnam
K
K
Amara
A
A
Arenzana-Seisdedos
F
F
Virelizier
J L
JL
Baggiolini
M
M
Sykes
B D
BD
Clark-Lewis
I
I
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D054377:Chemokine CXCL12; D018925:Chemokines / Q000819:agonists / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000494:pharmacology; D019743:Chemokines, CXC; D015497:HIV-1 / Q000187:drug effects*; D008954:Models, Biological; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D011487:Protein Conformation; D019718:Receptors, CXCR4 / Q000187:drug effects*; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; D019718:Receptors, CXCR4