): The first step in vision is the interaction of light with rhodopsin, a protein bound to a light absorbing chromophore, 11-cis retinal. Photo absorption causes retinal to convert from a cis to trans conformational change, and this change in structure is transmitted to the surrounding protein. A series of protein-protein interactions are altered by the structural change, and a G-protein cascade is induced, eventually leading to a nerve impulse. This process is very well studied and its role in human perception and disease is understood at the basic level. However, the three-dimensional, atomic level structure of rhodopsin is not yet known. This is because the protein is a transmembrane receptor. Membrane proteins are very difficult to study using NMR or X-ray crystallography, the latter because of difficulties in obtaining crystals. Recently, crystals of bovine rhodopsin have been generated that are the focus of this proposal. X-ray crystal structure analysis has been initiated using these crystals, and a low resolution structure is available confirming the presence of seven transmembrane helices. In this project, more ordered crystals will be grown to provide a higher resolution view of the structure, including the inter-membrane polypeptide loops important for interactions with G-proteins. Trapped photostates of rhodopsin, several of its derivatives with altered chromophores, and mutants for the protein will also be studied crystallographically. These three-dimensional molecular structures will be used to correlate the biochemical and biophysical information about rhodopsin and its interactions with other molecules. In addition, this first structure of a G-protein coupled receptor will provide a base for homology modeling of other members of this pharmaceutically important protein family.
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| Lodowski, David T; Salom, David; Le Trong, Isolde et al. (2007) Reprint of ""Crystal packing analysis of Rhodopsin crystals"" [J. Struct. Biol. 158 (2007) 455-462]. J Struct Biol 159:253-60 |
| Wu, Zhiping; Bhattacharya, Sanjoy K; Jin, Zhaoyan et al. (2006) CRALBP ligand and protein interactions. Adv Exp Med Biol 572:477-83 |
| Salom, David; Le Trong, Isolde; Pohl, Ehmke et al. (2006) Improvements in G protein-coupled receptor purification yield light stable rhodopsin crystals. J Struct Biol 156:497-504 |
| Nawrot, Maria; Liu, Tianyun; Garwin, Gregory G et al. (2006) Scaffold proteins and the regeneration of visual pigments. Photochem Photobiol 82:1482-8 |
| Fotiadis, Dimitrios; Jastrzebska, Beata; Philippsen, Ansgar et al. (2006) Structure of the rhodopsin dimer: a working model for G-protein-coupled receptors. Curr Opin Struct Biol 16:252-9 |
| Liu, Tianyun; Jenwitheesuk, Ekachai; Teller, David C et al. (2005) Structural insights into the cellular retinaldehyde-binding protein (CRALBP). Proteins 61:412-22 |
| Stenkamp, Ronald E; Teller, David C; Palczewski, Krzysztof (2005) Rhodopsin: a structural primer for G-protein coupled receptors. Arch Pharm (Weinheim) 338:209-16 |
| Wu, Zhiping; Hasan, Azeem; Liu, Tianyun et al. (2004) Identification of CRALBP ligand interactions by photoaffinity labeling, hydrogen/deuterium exchange, and structural modeling. J Biol Chem 279:27357-64 |
| Teller, David C; Stenkamp, Ronald E; Palczewski, Krzysztof (2003) Evolutionary analysis of rhodopsin and cone pigments: connecting the three-dimensional structure with spectral tuning and signal transfer. FEBS Lett 555:151-9 |
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