TY - JOUR

T1 - P-type ATPases as drug targets

T2 - Tools for medicine and science

AU - Yatime, Laure

AU - Buch-Pedersen, Morten J.

AU - Musgaard, Maria

AU - Morth, J. Preben

AU - Winther, Anne-Marie Lund

AU - Pedersen, Bjørn P.

AU - Olesen, Claus

AU - Andersen, Jens Peter

AU - Vilsen, Bente

AU - Schiøtt, Birgit

AU - Palmgren, Michael G.

AU - Møller, Jesper V.

AU - Nissen, Poul

AU - Fedosova, Natalya

PY - 2009

Y1 - 2009

N2 - P-type ATPases catalyze the selective active transport of ions like H+, Na+, K+, Ca2+, Zn2+, and Cu2+ across diverse biological membrane systems. Many members of the P-type ATPase protein family, such as the Na+,K+-, H+,K+-, Ca2+-, 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.

AB - P-type ATPases catalyze the selective active transport of ions like H+, Na+, K+, Ca2+, Zn2+, and Cu2+ across diverse biological membrane systems. Many members of the P-type ATPase protein family, such as the Na+,K+-, H+,K+-, Ca2+-, 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.

KW - Inhibitor

KW - Ion transport pathway

KW - P-type ATPases

KW - Pump

KW - Structure-based drug design

U2 - 10.1016/j.bbabio.2008.12.019

DO - 10.1016/j.bbabio.2008.12.019

M3 - Review

C2 - 19388138

AN - SCOPUS:61349128572

VL - 1787

SP - 207

EP - 220

JO - B B A - Bioenergetics

JF - B B A - Bioenergetics

SN - 0005-2728

IS - 4

ER -