Inward open characterization of EmrD transporter with molecular dynamics simulation

Tan, Xiaojie; Wang, Boxiong

doi:10.1016/j.bbrc.2016.04.006

Cited by 4 publications

(5 citation statements)

References 32 publications

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“…This could indicate that EmrD is able to simultaneously accommodate multiple substrates in the central cavity. 317 In the recently determined LmrP structure, 221 a lipid molecule was bound to the central cavity together with the substrate Hoechst 33342, which is a cell-permeable DNA staining dye. It is not fully understood but is plausible that specific lipids may control the substrate binding pocket itself, contributing further to substrate promiscuity.…”

Section: The Rocker-switch Mechanisms Of Mfs Multidrug Resistance (Mdr) Transportersmentioning

confidence: 99%

“…Intrinsic EmrD dynamics reveals states in which the cavity is wider than necessary for the substrate CCCP. This could indicate that EmrD is able to simultaneously accommodate multiple substrates in the central cavity . In the recently determined LmrP structure, a lipid molecule was bound to the central cavity together with the substrate Hoechst 33342, which is a cell-permeable DNA staining dye.…”

Section: The Rocker-switch Mechanisms Of Mfs Multidrug Resistance (Md...mentioning

confidence: 99%

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Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS)

et al. 2021

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The major facilitator superfamily (MFS) is the largest known superfamily of secondary active transporters. MFS transporters are responsible for transporting a broad spectrum of substrates, either down their concentration gradient or uphill using the energy stored in the electrochemical gradients. Over the last 10 years, more than a hundred different MFS transporter structures covering close to 40 members have provided an atomic framework for piecing together the molecular basis of their transport cycles. Here, we summarize the remarkable promiscuity of MFS members in terms of substrate recognition and proton coupling as well as the intricate gating mechanisms undergone in achieving substrate translocation. We outline studies that show how residues far from the substrate binding site can be just as important for fine-tuning substrate recognition and specificity as those residues directly coordinating the substrate, and how a number of MFS transporters have evolved to form unique complexes with chaperone and signaling functions. Through a deeper mechanistic description of glucose (GLUT) transporters and multidrug resistance (MDR) antiporters, we outline novel refinements to the rocker-switch alternating-access model, such as a latch mechanism for proton-coupled monosaccharide transport. We emphasize that a full understanding of transport requires an elucidation of MFS transporter dynamics, energy landscapes, and the determination of how rate transitions are modulated by lipids.

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Section: The Rocker-switch Mechanisms Of Mfs Multidrug Resistance (Mdr) Transportersmentioning

confidence: 99%

Section: The Rocker-switch Mechanisms Of Mfs Multidrug Resistance (Md...mentioning

confidence: 99%

Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS)

et al. 2021

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“…Detailed biochemical, biophysical, and structural investigations of the MFS antiporters MdfA, EmrD, YajR and SotB from E. coli and LmrP from L. lactis revealed that the substrate -H + coupling mechanism involves the sequential binding and release of substrate and proton. Both halves of the protein move correlatively similar to a rocker switch, arbitrated by salt bridge formation and breakage during the transport cycle (Jiang et al 2013;Wisedchaisri et al 2014;Zhang et al 2015;Tan and Wang 2016;Debruycker et al 2020;Xiao et al 2021;Drew et al 2021b). Further studies suggest that although proton translocation and substrate transport occur in distinct sites, they always compete for protein binding.…”

Section: Introductionmentioning

confidence: 92%

Spontaneous suppressors against debilitating transmembrane mutants of CaMdr1 disclose novel interdomain communication via Signature motifs of the Major Facilitator Superfamily

Sharma

Banerjee

Moréno

et al. 2022

Preprint

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The Major Facilitator Superfamily (MFS) includes multiple families of proteins operating as uniporters, symporters and antiporters for a wide spectrum of substrates. Among them, the multidrug resistance-1 drug:H+ antiporter CaMdr1 from Candida albicans is responsible for the efflux of structurally-diverse antifungals. MFS share a common fold of 12-14 transmembrane helices (TMHs) forming two N- and C-domains. Each domain is arranged in a pseudo symmetric fold of two tandems of 3-TMHs that alternatively expose the drug-binding site towards the inside or the outside of the yeast to promote drug binding and release. MFS show a high primary structure diversity and few conserved Signature motifs, each thought to have a common function in the superfamily, although not yet clearly established. Here, we provide new information on these motifs by having screened a library of 64 drug transport-deficient mutants and their corresponding suppressors spontaneously rescuing the deficiency. We found that five strains recovered the drug-resistance capacity by expressing CaMdr1 with a secondary mutation. The pairs of debilitating/rescuing residues are distributed either in the same TMH (T127ATMH1->G140DTMH1) or 3-TMHs repeat (F216ATMH4->G260ATMH5), at the hinge of 3-TMHs repeats tandems (R184ATMH3->D235HTMH4, L480ATMH10->A435TTMH9), and finally between the N- and C-domains (G230ATMH4->P528HTMH12). Remarkably, most of these mutants belongs to the different Signature motifs, highlighting a mechanistic role and interplay thought to be conserved among MFS. Results point also to the specific role of TMH11 in the interplay between the N- and C-domains in the inward- to outward-open conformational transition.

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“…Detailed biochemical, biophysical, and structural investigations of the MFS antiporters MdfA, EmrD, YajR, and SotB from E. coli and LmrP from Lactococcus lactis revealed that the substrate–H + coupling mechanism involves the sequential binding and release of substrate and proton. Both halves of the protein move correlatively similar to a rocker switch, arbitrated by salt bridge formation and breakage during the transport cycle [ 21 , 43 , 44 , 45 , 46 , 47 ]. Further studies suggest that although proton translocation and substrate transport occur in distinct sites, they always compete for protein binding.…”

Section: Introductionmentioning

confidence: 99%

Spontaneous Suppressors against Debilitating Transmembrane Mutants of CaMdr1 Disclose Novel Interdomain Communication via Signature Motifs of the Major Facilitator Superfamily

Sharma

Banerjee

Moréno

et al. 2022

JoF

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The Major Facilitator Superfamily (MFS) drug:H+ antiporter CaMdr1, from Candida albicans, is responsible for the efflux of structurally diverse antifungals. MFS members share a common fold of 12–14 transmembrane helices (TMHs) forming two N- and C-domains. Each domain is arranged in a pseudo-symmetric fold of two tandems of 3-TMHs that alternatively expose the drug-binding site towards the inside or the outside of the yeast to promote drug binding and release. MFS proteins show great diversity in primary structure and few conserved signature motifs, each thought to have a common function in the superfamily, although not yet clearly established. Here, we provide new information on these motifs by having screened a library of 64 drug transport-deficient mutants and their corresponding suppressors spontaneously addressing the deficiency. We found that five strains recovered the drug-resistance capacity by expressing CaMdr1 with a secondary mutation. The pairs of debilitating/rescuing residues are distributed either in the same TMH (T127ATMH1- > G140DTMH1) or 3-TMHs repeat (F216ATMH4- > G260ATMH5), at the hinge of 3-TMHs repeats tandems (R184ATMH3- > D235HTMH4, L480ATMH10- > A435TTMH9), and finally between the N- and C-domains (G230ATMH4- > P528HTMH12). Remarkably, most of these mutants belong to the different signature motifs, highlighting a mechanistic role and interplay thought to be conserved among MFS proteins. Results also point to the specific role of TMH11 in the interplay between the N- and C-domains in the inward- to outward-open conformational transition.

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Inward open characterization of EmrD transporter with molecular dynamics simulation

Cited by 4 publications

References 32 publications

Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS)

Structures and General Transport Mechanisms by the Major Facilitator Superfamily (MFS)

Spontaneous suppressors against debilitating transmembrane mutants of CaMdr1 disclose novel interdomain communication via Signature motifs of the Major Facilitator Superfamily

Spontaneous Suppressors against Debilitating Transmembrane Mutants of CaMdr1 Disclose Novel Interdomain Communication via Signature Motifs of the Major Facilitator Superfamily

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