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2VXW

Structural and Functional Studies of the Potent Anti-HIV Chemokine Variant P2-RANTES

Summary for 2VXW
Entry DOI10.2210/pdb2vxw/pdb
Related1B3A 1EQT 1HRJ 1RTN 1RTO 1U4L 1U4M 1U4P 1U4R
DescriptorC-C MOTIF CHEMOKINE 5 (2 entities in total)
Functional Keywordsimmune system, glycoprotein, cell-cell fusion, inflammatory response, hiv entry, chemotaxis
Biological sourceHOMO SAPIENS (HUMAN)
Cellular locationSecreted: P13501
Total number of polymer chains4
Total formula weight31672.48
Authors
Jin, H.,Li, P.,LiWang, P.J. (deposition date: 2008-07-12, release date: 2008-07-29, Last modification date: 2024-11-06)
Primary citationJin, H.,Kagiampakis, I.,Li, P.,Liwang, P.J.
Structural and Functional Studies of the Potent Anti-HIV Chemokine Variant P2-Rantes.
Proteins, 78:295-, 2010
Cited by
PubMed Abstract: The N-terminal region of the chemokine RANTES is critical for its function. A synthesized N-terminally modified analog of RANTES, P2-RANTES, was discovered using a phage display selection against living CCR5-expressing cells, and has been reported to inhibit HIV-1 env-mediated cell-cell fusion at subnanomolar levels (Hartley et al. J Virol 2003;77:6637-6644). In the present study we produced this protein using E. coli overexpression and extensively studied its structure and function. The x-ray crystal structure of P2-RANTES was solved and refined at 1.7 A resolution. This protein was found to be predominantly a monomer in solution by analytical ultracentrifugation, but a tetramer in the crystal. In studies of glycosaminoglycan binding, P2-RANTES was found to be significantly less able to bind heparin than wild type RANTES. We also tested this protein for receptor internalization where it was shown to be functional, in cell-cell fusion assays where recombinant P2-RANTES was a potent fusion inhibitor (IC(50) = 2.4 +/- 0.8 nM), and in single round infection assays where P2-RANTES inhibited at subnanomolar levels. Further, in a modified fusion assay designed to test specificity of inhibition, P2-RANTES was also highly effective, with a 65-fold improvement over the fusion inhibitor C37, which is closely related to the clinically approved inhibitor T-20. These studies provide detailed structural and functional information for this novel N-terminally modified chemokine mutant. This information will be very useful in the development of more potent anti-HIV agents. PDB Accession Number: 2vxw.
PubMed: 19722264
DOI: 10.1002/PROT.22542
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.7 Å)
Structure validation

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