Insights into How Nucleotide-Binding Domains Power ABC Transport

Newstead, Simon; Fowler, Philip W.; Bilton, Paul; Carpenter, E.P.; Sadler, Peter J.; Campopiano, Dominic J.; Sansom, Mark S. P.; Iwata, So

doi:10.1016/j.str.2009.07.009

Cited by 44 publications

(42 citation statements)

References 60 publications

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“…Starting from the crystal structure of maltose transporter in the OF state (45), a 100-ns simulation was performed after removing ATP from the two NBDs, as an efficient method to trigger the structural transition toward the IF state (46,47). The removal of ATP leads to a rapid separation of the NBDs, which in turn translates into the opening of the cytoplasmic ends of the closely coupled TM domains (47).…”

Section: Resultsmentioning

confidence: 99%

Transient formation of water-conducting states in membrane transporters

Shaikh

Enkavi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Membrane transporters rely on highly coordinated structural transitions between major conformational states for their function, to prevent simultaneous access of the substrate binding site to both sides of the membrane-a mode of operation known as the alternating access model. Although this mechanism successfully accounts for the efficient exchange of the primary substrate across the membrane, accruing evidence on significant water transport and even uncoupled ion transport mediated by transporters has challenged the concept of perfect mechanical coupling and coordination of the gating mechanism in transporters, which might be expected from the alternating access model. Here, we present a large set of extended equilibrium molecular dynamics simulations performed on several classes of membrane transporters in different conformational states, to test the presence of the phenomenon in diverse transporter classes and to investigate the underlying molecular mechanism of water transport through membrane transporters. The simulations reveal spontaneous formation of transient water-conducting (channel-like) states allowing passive water diffusion through the lumen of the transporters. These channel-like states are permeable to water but occluded to substrate, thereby not hindering the uphill transport of the primary substrate, i.e., the alternating access model remains applicable to the substrate. The rise of such water-conducting states during the large-scale structural transitions of the transporter protein is indicative of imperfections in the coordinated closing and opening motions of the cytoplasmic and extracellular gates. We propose that the observed water-conducting states likely represent a universal phenomenon in membrane transporters, which is consistent with their reliance on large-scale motion for function.major facilitator superfamily | LeuT-fold transporters | ABC transporters | neurotransmitter transporters

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Section: Resultsmentioning

confidence: 99%

Transient formation of water-conducting states in membrane transporters

Shaikh

Enkavi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…Moreover, since a few structures of transporters in the presence of nucleotides exist, valuable insights into possible conformational changes were gained and the basis for an understanding of their ATPdependent activity could be established [17][18][19][20][21]. In addition to static structural data, molecular dynamics (MD) simulations have been performed for the NBD components of various ABC transporters [22][23][24][25][26][27][28][29][30][31]. It is well established that binding of ATP causes closing of the NBDs and opening of them is obtained after ATP hydrolysis.…”

Section: Introductionmentioning

confidence: 99%

Nucleotide-Induced Conformational Dynamics in ABC Transporters from Structure-Based Coarse Grained Modeling

Flechsig

2016

Front. Phys.

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ATP-binding cassette (ABC) transporters are integral membrane proteins which mediate the exchange of diverse substrates across membranes powered by ATP molecules. Our understanding of their activity is still hampered since the conformational dynamics underlying the operation of such proteins cannot yet be resolved in detailed molecular dynamics studies. Here a coarse grained model which allows to mimic binding of nucleotides and follow subsequent conformational motions of full-length transporter structures in computer simulations is proposed and implemented. To justify its explanatory quality, the model is first applied to the maltose transporter system for which multiple conformations are known and we find that the model predictions agree remarkably well with the experimental data. For the MalK subunit the switching from open to the closed dimer configuration upon ATP binding is reproduced and, moreover, for the full-length maltose transporter, progression from inward-facing to the outward-facing state is correctly obtained. For the heme transporter HmuUV, for which only the free structure could yet be determined, the model was then applied to predict nucleotide-induced conformational motions. Upon binding of ATP-mimicking ligands the structure changed from a conformation in which the nucleotide-binding domains formed an open shape, to a conformation in which they were found in tight contact, while, at the same time, a pronounced rotation of the transmembrane domains was observed. This finding is supported by normal mode analysis, and, comparison with structural data of the homologous vitamin B 12 transporter BtuCD suggests that the observed rotation mechanism may contribute a common functional aspect for this class of ABC transporters. Although in HmuuV noticeable rearrangement of essential transmembrane helices was detected, there are no indications from our simulations that ATP binding alone may facilitate propagation of substrate molecules in this transporter. Possible explanations are discussed in the light of currently debated transport scenarios of ABC transporters.

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“…5 transporters comprise a large superfamily of transmembrane proteins that consists of both exporters and importers (1)(2)(3)(4)(5)(6)(7)(8)(9). ABC exporters are found in all domains of life and transport a variety of substrates, including lipids, peptides, toxins, antibiotics, and chemotherapeutic drugs (2).…”

Section: Abcmentioning

confidence: 99%

“…Periplasmic substrate-binding proteins (SBPs) deliver substrates to the inner membrane TMD-NBD complex, where conformational changes in the TMDs from inward to outward facing states facilitate payload acceptance. ATP hydrolysis in the NBDs leads to a reversal of these changes and subsequent substrate delivery from one leaflet of the lipid bilayer to the other (2)(3)(4)(5)(6)(7)(8)(9).…”

Section: Abcmentioning

confidence: 99%

In Vitro Reassembly of the Ribose ATP-binding Cassette Transporter Reveals a Distinct Set of Transport Complexes

Clifton

Simon

Erramilli

et al. 2015

Journal of Biological Chemistry

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Background:The ribose transporter is a bacterial ABC importer with a non-canonical organization. Results: The binding protein complexes with the membrane domain in the absence of substrate, and the ATPase dissociates from the membrane domain during transport. Conclusion: A distinct model for transport is proposed from in vitro reassembly conditions and EPR data. Significance: The ribose transporter typifies the diversity of ABC transporter mechanisms.

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Insights into How Nucleotide-Binding Domains Power ABC Transport

Cited by 44 publications

References 60 publications

Transient formation of water-conducting states in membrane transporters

Transient formation of water-conducting states in membrane transporters

Nucleotide-Induced Conformational Dynamics in ABC Transporters from Structure-Based Coarse Grained Modeling

In Vitro Reassembly of the Ribose ATP-binding Cassette Transporter Reveals a Distinct Set of Transport Complexes

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