The main goal of this proposal is to answer several unresolved fundamental questions regarding the structure and function of glutamate transporters. A series of experiments have been proposed to characterize the oligomeric structure of the functional transporters and to elucidate the structural features involved in subunit assembly and substrate selectivity.
Specific aim 1 will characterize the oligomeric structure of glutamate transporters and will utilize the differences between transporter subtypes to map domains necessary for subunit assembly. In addition, heteromultimerization of neuronal specific transporters will be examined. This is a critical experiment since it has been shown that EAAT3 and EAAT4 neuronal transporters are expressed together in the Purkinje cells of cerebellum. The mutagenesis and biochemical techniques described in this proposal will determine the amino acid residues necessary for substrate selectivity among transporters.
In specific aim 3, bacterial glutamate transporter will be purified in order to obtain x-ray diffractable crystals. Elucidating the molecular mechanisms underlying glutamate transporter function is essential in understanding synaptic transmission.
| Madani, Navid; Hubicki, Amy M; Perdigoto, Ana Luisa et al. (2007) Inhibition of human immunodeficiency virus envelope glycoprotein- mediated single cell lysis by low-molecular-weight antagonists of viral entry. J Virol 81:532-8 |
| Schon, Arne; Madani, Navid; Klein, Jeffrey C et al. (2006) Thermodynamics of binding of a low-molecular-weight CD4 mimetic to HIV-1 gp120. Biochemistry 45:10973-80 |
| Si, Zhihai; Madani, Navid; Cox, Jason M et al. (2004) Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins. Proc Natl Acad Sci U S A 101:5036-41 |
| Madani, Navid; Perdigoto, Ana Luisa; Srinivasan, Kumar et al. (2004) Localized changes in the gp120 envelope glycoprotein confer resistance to human immunodeficiency virus entry inhibitors BMS-806 and #155. J Virol 78:3742-52 |
