Total chemical synthesis and high-resolution crystal structure of the potent anti-HIV protein AOP-RANTES.

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

Total chemical synthesis and high-resolution crystal structure of the potent anti-HIV protein AOP-RANTES.

Chem Biol. 1999 Jan;6(1):43-51. Unique Identifier : AIDSLINE MED/99111238
Wilken J; Hoover D; Thompson DA; Barlow PN; McSparron H; Picard L; Wlodawer A; Lubkowski J; Kent SB; Gryphon Sciences, 250 East Grand Avenue, Suite 90, South San; Francisco,CA 94080, USA.

Abstract: BACKGROUND: RANTES is a CC-type chemokine protein that acts as a chemoattractant for several kinds of leukocytes, playing an important pro-inflammatory role. Entry of human immunodeficiency virus-1 (HIV-1) into cells depends on the chemokine receptor CCR5. RANTES binds CCR5 and inhibits HIV-1 entry into peripheral blood cells. Interaction with chemokine receptors involves a distinct set of residues at the amino terminus of RANTES. This finding was utilized in the development of a chemically modified aminooxypentane derivative of RANTES, AOP-RANTES, that was originally produced from the recombinant protein using semisynthetic methods. RESULTS: AOP-RANTES has been produced by a novel total chemical synthesis that provides efficient, direct access to large amounts of this anti-HIV protein analog. The crystal structure of chemically synthesized AOP-RANTES has been solved and refined at 1.6 A resolution. The protein is a dimer, with the amino-terminal pentane oxime moiety clearly defined. CONCLUSIONS: Total chemical synthesis of AOP-RANTES provides a convenient method of producing the multi-milligram quantities of this protein needed to investigate the molecular basis of receptor binding and antiviral activity. This work provides the first truly high-resolution structure of a RANTES protein, although the structure of RANTES was known from previous nuclear magnetic resonance (NMR) determinations.

Keywords: JOURNAL ARTICLE Amino Acid Sequence Anti-HIV Agents/CHEMISTRY/*CHEMICAL SYNTHESIS Crystallography, X-Ray Human Models, Molecular Molecular Sequence Data Nuclear Magnetic Resonance Peptides/CHEMISTRY/CHEMICAL SYNTHESIS Protein Conformation Protein Folding RANTES/*ANALOGS & DERIVATIVES/CHEMISTRY/CHEMICAL SYNTHESIS Support, Non-U.S. Gov't Support, U.S. Gov't, P.H.S.
990530
A9950919

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