The primary goal of our group continues to be development of structural models for the transmembrane portions of membrane proteins. Our most noted work has been on potassium channels and proteins, such as sodium and calcium channels and some active potassium transporters that evolved from them. The recent determination of a crystal structure of a bacterial potassium channel, KcsA, allows us to better evaluate our methods and results, and lets us move on to a more precise level of molecular modeling that may be useful for structure-based drug design. We are also using our modeling methods to predict how some channels open and close. Beginning with the crystal structure of the KcsA potassium channel, which is in a closed conformation, we are developing models of at least one member of every family of potassium channel in both open and closed conformations. We are also working on models of other types of channels that evolved from potassium channels such as calcium, sodium, and cyclic nucleotide-gated channels. Likewise, beginning with the crystal structure of a closed mechanosensitive channel, mscL, we have developed models for an open conformation and numerous conformations that are intermediate between the closed and open conformations. Our collaborator, Sergei Sukharev, has experimentally verified several aspects of these models. We are also beginning projects to analyze two new categories of proteins for which a crystal structure has been solved. These are G protein coupled receptors (rhodopsin was solved) and ion pumps (a calcium pump structure was solved). These studies should help us evaluate and better quantify our modeling criteria. Z01 BC 08363-17

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC008363-19
Application #
6558999
Study Section
(LECB)
Project Start
Project End
Budget Start
Budget End
Support Year
19
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Tseng, Gea-Ny; Guy, H Robert (2005) Structure-function studies of the outer mouth and voltage sensor domain of hERG. Novartis Found Symp 266:19-35; discussion 35-45
Guy, H Robert (2005) Transmembrane interactions of alpha/beta integrin signaling. Structure 13:683-4
Durell, Stewart R; Shrivastava, Indira H; Guy, H Robert (2004) Models of the structure and voltage-gating mechanism of the shaker K+ channel. Biophys J 87:2116-30
Shafrir, Yinon; Guy, H Robert (2004) STAM: simple transmembrane alignment method. Bioinformatics 20:758-69
Shrivastava, Indira H; Durell, Stewart R; Guy, H Robert (2004) A model of voltage gating developed using the KvAP channel crystal structure. Biophys J 87:2255-70
Durell, S R; Bakker, E P; Guy, H R (2000) Does the KdpA subunit from the high affinity K(+)-translocating P-type KDP-ATPase have a structure similar to that of K(+) channels? Biophys J 78:188-99
Cho, H C; Tsushima, R G; Nguyen, T T et al. (2000) Two critical cysteine residues implicated in disulfide bond formation and proper folding of Kir2.1. Biochemistry 39:4649-57