ABCMdb

ABCB1 p.Met949Arg

Predicted by SNAP2:	A: D (53%), C: D (53%), D: D (85%), E: D (85%), F: D (53%), G: D (59%), H: D (59%), I: N (82%), K: D (80%), L: N (53%), N: D (59%), P: D (71%), Q: D (59%), R: D (75%), S: N (53%), T: N (53%), V: N (72%), W: D (85%), Y: D (53%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: N, G: D, H: D, I: N, K: D, L: N, N: D, P: D, Q: D, R: D, S: D, T: D, V: N, W: D, Y: D,

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Publications
[hide] Mapping the Binding Site of the Inhibitor Tariquid... J Biol Chem. 2015 Dec 4;290(49):29389-401. doi: 10.1074/jbc.M115.695171. Epub 2015 Oct 26. Loo TW, Clarke DM
Mapping the Binding Site of the Inhibitor Tariquidar That Stabilizes the First Transmembrane Domain of P-glycoprotein.
J Biol Chem. 2015 Dec 4;290(49):29389-401. doi: 10.1074/jbc.M115.695171. Epub 2015 Oct 26., [PMID:26507655]

Abstract [show]
ABC (ATP-binding cassette) transporters are clinically important because drug pumps like P-glycoprotein (P-gp, ABCB1) confer multidrug resistance and mutant ABC proteins are responsible for many protein-folding diseases such as cystic fibrosis. Identification of the tariquidar-binding site has been the subject of intensive molecular modeling studies because it is the most potent inhibitor and corrector of P-gp. Tariquidar is a unique P-gp inhibitor because it locks the pump in a conformation that blocks drug efflux but activates ATPase activity. In silico docking studies have identified several potential tariquidar-binding sites. Here, we show through cross-linking studies that tariquidar most likely binds to sites within the transmembrane (TM) segments located in one wing or at the interface between the two wings (12 TM segments form 2 divergent wings). We then introduced arginine residues at all positions in the 12 TM segments (223 mutants) of P-gp. The rationale was that a charged residue in the drug-binding pocket would disrupt hydrophobic interaction with tariquidar and inhibit its ability to rescue processing mutants or stimulate ATPase activity. Arginines introduced at 30 positions significantly inhibited tariquidar rescue of a processing mutant and activation of ATPase activity. The results suggest that tariquidar binds to a site within the drug-binding pocket at the interface between the TM segments of both structural wings. Tariquidar differed from other drug substrates, however, as it stabilized the first TM domain. Stabilization of the first TM domain appears to be a key mechanism for high efficiency rescue of ABC processing mutants that cause disease.

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No. Sentence Comment
188 These were in TM7 (Q725R, F728R, and F732R) (Fig. 6A), TM10 (V865R, I868R, and G872R) (Fig. 6D), TM11 (F942R, T945R, Q946R, M949R, Y950R, and Y953R) (Fig. 6E), and TM12 (L975R, F978R, and V982R) (Fig. 6F). Login to comment
194 The other 12 mutants in TM1 (F72R), TM5 (Y307R and Y310R), TM6 (F336R and F343R), TM7 (F732R), TM10 (V865R), TM11 (M949R, Y950R, S952R, and Y953R), and TM12 (L975R and F978R) were not rescued by cyclosporine A (Fig. 7). Login to comment
212 Seventeen of the 30 G251V/arginine mutants (M68R, M69R, and F72R in TM1; I306R, Y307R, S309R, and Y310R in TM5; F336R in TM6; F728R and F732R in TM7; I868R and G872R in TM10; F942R, T945R, M949R, and S952R in TM11; and V982R in TM12) that could not be rescued with tariquidar showed little or no stimulation of ATPase activity with tariquidar (Fig. 8A). Login to comment