The androgen receptor (AR) is essential for the growth of prostate cancer cells. Here, we report that tyrosine phosphorylation of AR is induced by growth factors and elevated in hormone-refractory prostate tumors. Mutation of the major tyrosine phosphorylation site in AR significantly inhibits the growth of prostate cancer cells under androgen-depleted conditions. The Src tyrosine kinase appears to be responsible for phosphorylating AR, and there is a positive correlation of AR tyrosine phosphorylation with Src tyrosine kinase activity in human prostate tumors. Our data collectively suggest that growth factors and their downstream tyrosine kinases, which are elevated during hormone-ablation therapy, can induce tyrosine phosphorylation of AR and such modification may be important for prostate tumor growth under androgen-depleted conditions.

(transmembrane subunit of HIV envelope) and gp120 (surface envelope glycoprotein of HIV) (1). Both proteins therefore present highly attractive targets for the development of antiviral agents as well as broadly neutralizing antibodies. HIV Envmediated cell fusion involves a complex series of events. gp120 first binds to CD4 and a chemokine receptor; this triggers conformational changes in the gp120-gp41 complex that lead to the insertion of the gp41 fusion peptide into the target membrane and ultimately to cell fusion (2, 3).The structure of the ectodomain of gp41 (e-gp41) in its fusogenic/post-fusogenic state has been solved by both NMR (4) and crystallography (5-8) and consists of a trimer of hairpins comprising an internal parallel trimeric coiled-coil of N-terminal helices (residues 542-592 of HIV-1 Env (4)) surrounded by antiparallel C-terminal helices (residues 623-663 of HIV-1 Env (4)) (left-hand side of Fig. 1). The formation of the fusogenic/post-fusogenic state of e-gp41 provides the driving force for the apposition of the virus and cell membranes, thereby promoting membrane fusion (2). Prior to the formation of the fusogenic trimer of hairpins, e-gp41 exists in a "prehairpin" intermediate state (2, 9 -12), so-called because the C region of e-gp41 (corresponding to the C-helices in the fusogenic/postfusogenic state) is not yet associated with the internal trimeric coiled-coil of N-helices (Fig. 1, middle). In the prehairpin intermediate state both the internal trimeric coiled-coil (9, 10) and the C region of e-gp41 are accessible to inhibitors (13-15).There are three classes of fusion inhibitors that target the prehairpin intermediate state of e-gp41 (right-hand side of Fig. 1). Class 1 inhibitors (shown in blue at the top right of Fig. 1) are directed against the internal trimeric coiled-coil of N-helices. Examples of class 1 inhibitors include peptides derived from the C-helices such as C34 (residues 628 -661 of HIV-1 Env) 2 and T20 (also referred to as DP178, residues 638 -673 of HIV-1 Env which extends 10 residues beyond the C-terminal end of the C-helix), both of which have IC 50 values in the low nanomolar range (16 -18). T20 is currently in the final stages of * This work was supported by the Intramural AIDS Targeted Antiviral Program of the Office of the Director of the National Institutes of Health (to G. M. C. and C. A. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.‡ To whom correspondence may be addressed: Laboratory of Chemical Physics, Bldg. 5, Rm. B1-30I, NIDDK, National Institutes of Health, Bethesda, MD 20892-0510. Tel.: 301-496-0782; Fax: 301-496-0825; E-mail: mariusc@intra.niddk.nih.gov. § To whom correspondence may be addressed: Laboratory of Bioorganic Chemistry, Bldg. 8, Rm. 1A-02, NIDDK, National Institutes of Health, Bethesda, MD 20892-0820. Tel.: 301-594-5187; E-mail: cb194k@nih.gov. 1 The...

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Interactions between the C-terminal interface residues (96 -99) of the mature HIV-1 protease were shown to be essential for dimerization, whereas the N-terminal residues (1-4) and Arg 87 contribute to dimer stability (Ishima, R., Ghirlando, R., Tozser, J., Gronenborn, A.