- ADJUNCT ASSOCIATE PROFESSOR Neuroscience
- ADJUNCT ASSOCIATE PROFESSOR Structural and Chemical Biology
The Roche Institute for Molecular Biology
Ph.D., University of Virginia
- Visit Dr. Marianna Max's Lab for more information.
ResearchSpecific Clinical/Research Interest:
G-protein coupled receptors for sweet taste transduction .
Current Students: Elvera Baron
Research Personnel: Radjou.Benard
My research focuses on structure/function relationships of sensory receptors and their ligands and the underlying molecular transduction events that lead to stimulation of our senses. I have focused on two modalities in two sensory systems: light sensing for the circadian system and sweet ligand sensing by the taste system.
More recently, my research has been directed towards the sweet taste receptor, which is a heterodimer of two Family C GPCRs, T1R2 and T1R3., T1R3 was discovered by me in 2001 using a bioinformatic approach, and characterized in my lab (Max et al., 2001) as well as independently in other labs (Kitagawa et al., 2001; Montmayeur et al., 2001; Sainz et al., 2001; Nelson et al., 2001; Bachmanov et al., 2001).
Each monomer of the sweet receptor has three distinct domains; The extracellular venus fly trap module (VFTM) is composed of two lobes that open and close around a cleft that, we have shown (Maillet et al., in preparation), binds some of the sweet ligands. The transmembrane domain (TMD) is a fairly typical seven membrane span segment that likely has structural homology and some conserved microdomains with the family A rhodopsin-like GPCRs (Baron et al., in preparation) and binding sites for agonists and antagonists (Jiang et al., 2005a,b). There is a linking domain between the VFTM and the TMD that is rich in conserved cysteines called the CRD which also has been shown to be important, along with the VFTM, for binding sweet tasting proteins such as brazzein and monellin (Jiang et al., 2004 Max, Maillet & Assadi - Porter, in prep).
Currently, my collaborators and I are working together to understand how the sweet receptor binds multiple sweet ligands to form the active complex that interacts with G-proteins. We are using a combined approach of STD-NMR, molecular modeling, biophysics, biochemisty, mutagenesis and heterologous expression to investigate each domain of the sweet receptor for ligand binding sites (Assadi-Porter et al., 2008).
Visit Dr. Marianna Max's Lab for more information.
Li DF, Jiang P, Zhu DY, Hu Y, Max M, Wang DC. Crystal structure of Mabinlin II: a novel structural type of sweet protein and the main structural basis for its sweetness. J Struct Biol 2008; 162: 50-62.
Assadi-Porter FM, Tonelli M, Maillet E, Hallenga K, Max M, Markley JL. Direct ligand binding interaction studies with the sweet heteroreceptors, a Family 3 GPCR protein, by NMR spectroscopy. J Am Chem Soc 2008; 11: 647-658.
Cui M, Jiang P, Max M, Maillet M, Margolskee RF, Osman R. The heterodimeric sweet taste receptor has multiple potential ligand binding sites. Current Pharmacutical Design 2006; 12(35): 4591-4600.
Jiang P, Cui M, Zhao B, Liu Z, Snyder L, Bernard L, Osman R, Max M, Margolskee RF. Identification of the cyclamate interaction site within the transmembrane domain of the human sweet taste receptor subunit T1R3. J Biol Chem 2005; 280(40): 34296-34305.
Jiang P, Cui M, Zhao B, Liu Z, Snyder L, Bernard L, Osman R, Margolskee RF, Max M. Lactisole interacts with the transmembrane regions of human T1R3 to inhibit sweet taste. J. Biol Chem 2005; 280(15): 15238-1546.
Jiang P, Ji Q, Liu Z, Benard L, Margolskee RF, Snyder L, Max M. The Cysteine-rich Region of T1R3 Determines Responses to Intensely Sweet Proteins. J Biol Chem 2004; 279: 45068-45075.
Perez CA, Huang L, Rong M, Kozak JA, Preuss AK, Max M, Margolskee RF. Identification of a TRP channel in a subset of taste receptor cells. Nat Neurosci 2002; 11: 1169-1176.
Max M, Shanker YG, Rong M, Liu Z, Campagne F, Weinstein H, Damak S, Margolskee RF. Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac. Nat Genet 2001 May; 28(1): 58-63.The ability to taste the sweetness of carbohydrate-rich foodstuffs has a critical role in the nutritional status of humans. Although several components of bitter transduction pathways have been identified, the receptors and other sweet transduction elements remain unknown. The Sac locus in mouse, mapped to the distal end of chromosome 4 (refs. 7-9), is the major determinant of differences between sweet-sensitive and -insensitive strains of mice in their responsiveness to saccharin, sucrose and other sweeteners. To identify the human Sac locus, we searched for candidate genes within a region of approximately one million base pairs of the sequenced human genome syntenous to the region of Sac in mouse. From this search, we identified a likely candidate: T1R3, a previously unknown G protein-coupled receptor (GPCR) and the only GPCR in this region. Mouse Tas1r3 (encoding T1r3) maps to within 20,000 bp of the marker closest to Sac (ref. 9) and, like human TAS1R3, is expressed selectively in taste receptor cells. By comparing the sequence of Tas1r3 from several independently derived strains of mice, we identified a specific polymorphism that assorts between taster and non-taster strains. According to models of its structure, T1r3 from non-tasters is predicted to have an extra amino-terminal glycosylation site that, if used, would interfere with dimerization.
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