ABCMdb

ABCB3 p.Val656Leu

Predicted by SNAP2:	A: N (57%), C: N (72%), D: D (75%), E: D (71%), F: D (66%), G: D (66%), H: D (66%), I: N (87%), K: D (71%), L: N (87%), M: N (57%), N: D (66%), P: D (75%), Q: D (66%), R: D (71%), S: N (66%), T: N (78%), W: D (75%), Y: D (71%),
Predicted by PROVEAN:	A: D, C: D, D: D, E: D, F: D, G: D, H: D, I: N, K: D, L: N, M: N, N: D, P: D, Q: D, R: D, S: D, T: D, W: D, Y: D,

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Publications
[hide] The multidrug transporter Pdr5 on the 25th anniver... Biochem J. 2015 May 1;467(3):353-63. doi: 10.1042/BJ20150042. Golin J, Ambudkar SV
The multidrug transporter Pdr5 on the 25th anniversary of its discovery: an important model for the study of asymmetric ABC transporters.
Biochem J. 2015 May 1;467(3):353-63. doi: 10.1042/BJ20150042., [PMID:25886173]

Abstract [show]
Asymmetric ABC (ATP-binding cassette) transporters make up a significant proportion of this important superfamily of integral membrane proteins. These proteins contain one canonical (catalytic) ATP-binding site and a second atypical site with little enzymatic capability. The baker's yeast (Saccharomyces cerevisiae) Pdr5 multidrug transporter is the founding member of the Pdr subfamily of asymmetric ABC transporters, which exist only in fungi and slime moulds. Because these organisms are of considerable medical and agricultural significance, Pdr5 has been studied extensively, as has its medically important homologue Cdr1 from Candida albicans. Genetic and biochemical analyses of Pdr5 have contributed important observations that are likely to be applicable to mammalian asymmetric ABC multidrug transporter proteins, including the basis of transporter promiscuity, the function of the non-catalytic deviant ATP-binding site, the most complete description of an in vivo transmission interface, and the recent discovery that Pdr5 is a molecular diode (one-way gate). In the present review, we discuss the observations made with Pdr5 and compare them with findings from clinically important asymmetric ABC transporters, such as CFTR (cystic fibrosis transmembrane conductance regulator), Cdr1 and Tap1/Tap2.

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Sentences [show]
No. Sentence Comment
160 Perhaps the most important mutant in the collection was a V656L substitution that lies in cis orientation in ICL2 with respect to the Q-loop [19,20]. Login to comment
165 Further evidence for the cis interface came from our observation that V656L was also a strong suppressor of the cis Q-loop drug-hypersensitive mutation E244G. Login to comment
200 Therefore these mutants altered the stimulation signal, much like S558Y, V656L and V656A altered the trans-inhibition of Pdr5 ATPase by clotrimazole [18-20]. Login to comment
208 Three, V656L, P596L and A670S, were in regions making up the predicted Pdr5 signal interface (V656L and P596L were also represented in our suppressor mutant hunt). Login to comment
209 Clues about how these alleles might manipulate the interface to create greater drug resistance came from our in-depth study of V656L [20]. Login to comment
213 Furthermore, whereas the V656L suppression of E244G restored drug-resistance to WT levels, the reduced level of ATPase activity seen in the E244G mutant remained. Login to comment
214 Taken together, the behaviour of V656L and the E244G/V656L double mutant suggested that the V656L substitution increased resistance in one of two ways. It is plausible that the V656L mutant increases the efficiency with which the energy from ATP binding and/or hydrolysis is used for transport. Login to comment