October 8, 2010
New GPCR Structure: CXCR4 Chemokine Receptor (HIV and Cancer Target)
Congratulations to Ray Stevens and team to determining and publishing the crystallographic structure of the CXCR4 Chemokine receptor in Science. The diffenent binding areas for the small molecule and peptide antagonist are nicely resolved and show extensive interactions with binding pocket residues in the 2.5 - 3.1 A crystal structures.
Wu B, Chien EY, Mol CD, Fenalti G, Liu W, Katritch V, Abagyan R, Brooun A, Wells P, Bi FC, Hamel DJ, Kuhn P, Handel TM, Cherezov V, & Stevens RC (2010). Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists. Science (New York, N.Y.), 330 (6007), 1066-71 PMID: 20929726
The corresponding structure files have not been released as of writing this. The PDB accession codes are: 3ODU (CXCR4-2–IT1t,P21), 3OE0 (CXCR4-3–CVX15, C2), 3OE8 (CXCR4-2–IT1t, P1), 3OE9 (CXCR4-3–IT1t, P1), and 3OE6 (CXCR4-1–IT1t, I222). The supplemental material lists a protocol that one could almost characterize as becoming 'the standard' for GPCR structure studies: expression of highly engineered construct (5 features) in Sf9 cells, membranes solubilized with a mix of dodecylmaltoside and cholesterol hemisuccinate (no detergent exchange) , His tag clipped off, PNGase treatment and crystallization in a matrix consisting of monoolein-based LCP with 6% cholesterol. All five crystal forms are stacked layers of membranes (as expected in LCP - grown crystals).
Lots of info to digest. What a feast!
Peter