P-type ATPases as drug targets: Tools for medicine and science

• Published in: Biochimica et biophysica acta 2009-04, Vol.1787 (4), p.207-220
• Main Authors: Yatime, Laure, Buch-Pedersen, Morten J., Musgaard, Maria, Morth, J. Preben, Winther, Anne-Marie Lund, Pedersen, Bjørn P., Olesen, Claus, Andersen, Jens Peter, Vilsen, Bente, Schiøtt, Birgit, Palmgren, Michael G., Møller, Jesper V., Nissen, Poul, Fedosova, Natalya
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - chemistry; Animals; Biochemistry, Molecular Biology; Humans; Inhibitor; Ion transport pathway; Life Sciences; Medicine; Models, Molecular; P-type ATPases; Pharmaceutical Preparations; Proton Pump Inhibitors; Proton Pumps - chemistry; Pump; Science; Structural Biology; Structure-based drug design
• ISSN: 0005-2728; 0006-3002; 1879-2650
• DOI: 10.1016/j.bbabio.2008.12.019

P-type ATPases catalyze the selective active transport of ions like H +, Na +, K +, Ca 2+, Zn 2+, and Cu 2+ across diverse biological membrane systems. Many members of the P-type ATPase protein family, such as the Na +,K +-, H +,K +-, Ca 2+-, and H +-ATPases, are involved in the development of pathophysiological conditions or provide critical function to pathogens. Therefore, they seem to be promising targets for future drugs and novel antifungal agents and herbicides. Here, we review the current knowledge about P-type ATPase inhibitors and their present use as tools in science, medicine, and biotechnology. Recent structural information on a variety of P-type ATPase family members signifies that all P-type ATPases can be expected to share a similar basic structure and a similar basic machinery of ion transport. The ion transport pathway crossing the membrane lipid bilayer is constructed of two access channels leading from either side of the membrane to the ion binding sites at a central cavity. The selective opening and closure of the access channels allows vectorial access/release of ions from the binding sites. Recent structural information along with new homology modeling of diverse P-type ATPases in complex with known ligands demonstrate that the most proficient way for the development of efficient and selective drugs is to target their ion transport pathway.