First Protein Structure of
a Key Molecular Engine
Researchers from Berkeley Lab and the University of California, Berkeley, have used the Macromolecular Crystallography Facility at the ALS to obtain the crystal structure of the HisP subunit of histidine permease, an ABC transporter in the bacterium Salmonella typhimurium. ABC transporters are proteins responsible for movement of biochemical compounds through cell membranes in both prokaryotes and eukaryotes. The structure provides a basis for understanding properties of both normal and defective ABC transporters.
(left) Histidine permease (HisQMP2) molecular pump in a cell membrane (green) consists of two membrane-spanning domains (HisQ and HisM) and two identical nucleotide-binding domains (HisP). (right) Operation of the pump is driven by binding of adenosine triphosphate (ATP) and hydrolysis to adenosine diphosphate (ADP), which are proposed to cause conformational changes in HisP that are transmitted to HisQ and HisP.
Structure of the HisP nucleotide-binding domain in histidine permease obtained with a resolution of 1.5 Å consists of two arms in an L-shaped configuration. ATP (shown in ball-and-stick representation) resides in a binding pocket toward the bottom of Arm I. Two HisP units together form a dimer.
ABC transporters are increasingly recognized as the causes of genetic diseases in humans. For example, mutations in the gene that codes for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis. The Berkeley researchers used their HisP findings to propose a structural basis for the consequences of the known mutations of CFTR. This kind of information may eventually lead to a treatment for cystic fibrosis.
Research conducted by L.-W. Hung (Berkeley Lab); I. X. Wang, K. Nikaido, P.-Q. Liu, and G. F.-L. Ames (University of California, Berkeley); and S.-H. Kim (University of California, Berkley, and Berkeley Lab), using Beamline 5.0.2.
Funding: U. S. Department of Energy, Office of Biological and Environmental Research; National Institutes of Health.
Publication about this experiment: L.-W. Hung et al., Nature 396, 703 (1998).
ALSNews article about this science highlight
More ALS Science