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001-es BibID:BIBFORM088874
035-os BibID:(cikkazonosító)e1009016 (WoS)000581778600004 (Scopus)85092684596
Első szerző:Goda Katalin (biofizikus)
Cím:Human ABCB1 with an ABCB11-like degenerate nucleotide binding site maintains transport activity by avoiding nucleotide occlusion / Goda Katalin, Dönmez-Cakil Yaprak, Tarapcsák Szabolcs, Szalóki Gábor, Szöllősi Dániel, Parveen Zahida, Türk Dóra, Szakács Gergely, Chiba Peter, Stockner Thomas
Dátum:2020
ISSN:1553-7390 1553-7404
Megjegyzések:Several ABC exporters carry a degenerate nucleotide binding site (NBS) that is unable to hydrolyze ATP at a rate sufficient for sustaining transport activity. A hallmark of a degenerate NBS is the lack of the catalytic glutamate in the Walker B motif in the nucleotide binding domain (NBD). The multidrug resistance transporter ABCB1 (P-glycoprotein) has two canonical NBSs, and mutation of the catalytic glutamate E556 in NBS1 renders ABCB1 transport-incompetent. In contrast, the closely related bile salt export pump ABCB11 (BSEP), which shares 49% sequence identity with ABCB1, naturally contains a methionine in place of the catalytic glutamate. The NBD-NBD interfaces of ABCB1 and ABCB11 differ only in four residues, all within NBS1. Mutation of the catalytic glutamate in ABCB1 results in the occlusion of ATP in NBS1, leading to the arrest of the transport cycle. Here we show that despite the catalytic glutamate mutation (E556M), ABCB1 regains its ATP-dependent transport activity, when three additional diverging residues are also replaced. Molecular dynamics simulations revealed that the rescue of ATPase activity is due to the modified geometry of NBS1, resulting in a weaker interaction with ATP, which allows the quadruple mutant to evade the conformationally locked pre-hydrolytic state to proceed to ATP-driven transport. In summary, we show that ABCB1 can be transformed into an active transporter with only one functional catalytic site by preventing the formation of the ATP-locked pre-hydrolytic state in the non-canonical site.
Tárgyszavak:Orvostudományok Elméleti orvostudományok idegen nyelvű folyóiratközlemény külföldi lapban
folyóiratcikk
Human ABCB1 transport
nucleotide binding
Megjelenés:Plos Genetics. - 16 : 10 (2020), p. 1-21. -
További szerzők:Dönmez-Cakil, Yaprak Tarapcsák Szabolcs (1989-) (Molekuláris biológus) Szalóki Gábor (1986-) (molekuláris biológus) Szöllősi Dániel Parveen, Zahida Türk Dóra Szakács Gergely Chiba, Peter Stockner, Thomas
Pályázati támogatás:K124815
NKFIH
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