Three-Dimensional Quantitative Structure-Activity Relationship Study of the Inhibition of Na+,K+-ATPase by Cardiotonic Steroids Using Comparative Molecular Field Analysis
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- 作者：Carol D. Farr ; Craig Burd ; Michael R. Tabet ; Xia Wang ; William J. Welsh ; and William J. Ball ; Jr.
- 刊名：Biochemistry
- 出版年：2002
- 出版时间：January 29, 2002
- 年：2002
- 卷：41
- 期：4
- 页码：1137 - 1148
- 全文大小：435K
- 年卷期：v.41,no.4(January 29, 2002)
- ISSN：1520-4995
文摘
Na+,K+-ATPase is a transmembrane protein that transports sodium and potassium ions acrosscell membranes during an activity cycle that uses the energy released by ATP hydrolysis. Cardiotonicsteroids (digitalis) inhibit this activity and consequently produce a positive inotropic response in the heart.To identify the structural features of the steroids that are important for this inhibition, we have tested theinhibitory properties of 47 cardiotonic and hormonal steroids and developed a three-dimensional quantitativestructure-activity relationship (3D-QSAR) model for the inhibition of Na+,K+-ATPase using comparativemolecular field analysis (CoMFA). We also developed a 3D-QSAR model for the binding of digoxin tothe murine anti-digoxin monoclonal antibody (mAb) 26-10 because we have previously shown that theenvironment of the binding sites of 26-10 and the enzyme are similar (Kasturi et al. (1998) Biochemistry37, 6658-6666). These statistically predictive 3D-QSAR models indicate that both binding sites are about20 Å long and have a close fit or complementarity about the 
side of the lactone ring of digitalis.Furthermore, steric bulk about the lactone ring and the 
sugar may be critical for drug binding. However,the binding site of Na+,K+-ATPase differs from that of mAb in that it has a greater number of electrostaticinteractions along the -sugar, steroid, and lactone moieties. In addition, the availability of the structureof the 26-10 Fab-digoxin complex (Jeffrey et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 10310-10314)enabled us to compare the CoMFA-derived contour maps with the known locations for amino acid residuescomprising the mAb ligand binding site.
side of the lactone ring of digitalis.Furthermore, steric bulk about the lactone ring and the sugar may be critical for drug binding. However,the binding site of Na+,K+-ATPase differs from that of mAb in that it has a greater number of electrostaticinteractions along the -sugar, steroid, and lactone moieties. In addition, the availability of the structureof the 26-10 Fab-digoxin complex (Jeffrey et al. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 10310-10314)enabled us to compare the CoMFA-derived contour maps with the known locations for amino acid residuescomprising the mAb ligand binding site.