Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter

Simone Weyand; Tatsuro Shimamura; Shunsuke Yajima; Shun'ichi Suzuki; Osman Asghar Mirza; Kuakarun Krusong; Elisabeth P Carpenter; Nicholas G Rutherford; Jonathan M Hadden; John O'Reilly; Pikyee Ma; Massoud Saidijam; Simon G Patching; Ryan J Hope; Halina T Norbertczak; Peter C J Roach; So Iwata; Peter J F Henderson; Alexander D Cameron

doi:10.1126/science.1164440

Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter

Simone Weyand, Tatsuro Shimamura, Shunsuke Yajima, Shun'ichi Suzuki, Osman Asghar Mirza, Kuakarun Krusong, Elisabeth P Carpenter, Nicholas G Rutherford, Jonathan M Hadden, John O'Reilly, Pikyee Ma, Massoud Saidijam, Simon G Patching, Ryan J Hope, Halina T Norbertczak, Peter C J Roach, So Iwata, Peter J F Henderson, Alexander D Cameron

275 Citations (Scopus)

Abstract

The nucleobase-cation-symport-1 (NCS1) transporters are essential components of salvage pathways for nucleobases and related metabolites. Here, we report the 2.85-angstrom resolution structure of the NCS1 benzyl-hydantoin transporter, Mhp1, from Microbacterium liquefaciens. Mhp1 contains 12 transmembrane helices, 10 of which are arranged in two inverted repeats of five helices. The structures of the outward-facing open and substrate-bound occluded conformations were solved, showing how the outward-facing cavity closes upon binding of substrate. Comparisons with the leucine transporter LeuT(Aa) and the galactose transporter vSGLT reveal that the outward- and inward-facing cavities are symmetrically arranged on opposite sides of the membrane. The reciprocal opening and closing of these cavities is synchronized by the inverted repeat helices 3 and 8, providing the structural basis of the alternating access model for membrane transport.

Original language	English
Journal	Science
Volume	322
Issue number	5902
Pages (from-to)	709-713
ISSN	0036-8075
DOIs	https://doi.org/10.1126/science.1164440
Publication status	Published - 2008

Keywords

Former Faculty of Pharmaceutical Sciences

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Weyand, S., Shimamura, T., Yajima, S., Suzuki, S., Mirza, O. A., Krusong, K., Carpenter, E. P., Rutherford, N. G., Hadden, J. M., O'Reilly, J., Ma, P., Saidijam, M., Patching, S. G., Hope, R. J., Norbertczak, H. T., Roach, P. C. J., Iwata, S., Henderson, P. J. F., & Cameron, A. D. (2008). Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter. Science, 322(5902), 709-713. https://doi.org/10.1126/science.1164440

Weyand, S, Shimamura, T, Yajima, S, Suzuki, S, Mirza, OA, Krusong, K, Carpenter, EP, Rutherford, NG, Hadden, JM, O'Reilly, J, Ma, P, Saidijam, M, Patching, SG, Hope, RJ, Norbertczak, HT, Roach, PCJ, Iwata, S, Henderson, PJF & Cameron, AD 2008, 'Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter', Science, vol. 322, no. 5902, pp. 709-713. https://doi.org/10.1126/science.1164440

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title = "Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter",

abstract = "The nucleobase-cation-symport-1 (NCS1) transporters are essential components of salvage pathways for nucleobases and related metabolites. Here, we report the 2.85-angstrom resolution structure of the NCS1 benzyl-hydantoin transporter, Mhp1, from Microbacterium liquefaciens. Mhp1 contains 12 transmembrane helices, 10 of which are arranged in two inverted repeats of five helices. The structures of the outward-facing open and substrate-bound occluded conformations were solved, showing how the outward-facing cavity closes upon binding of substrate. Comparisons with the leucine transporter LeuT(Aa) and the galactose transporter vSGLT reveal that the outward- and inward-facing cavities are symmetrically arranged on opposite sides of the membrane. The reciprocal opening and closing of these cavities is synchronized by the inverted repeat helices 3 and 8, providing the structural basis of the alternating access model for membrane transport.",

keywords = "Former Faculty of Pharmaceutical Sciences",

author = "Simone Weyand and Tatsuro Shimamura and Shunsuke Yajima and Shun'ichi Suzuki and Mirza, {Osman Asghar} and Kuakarun Krusong and Carpenter, {Elisabeth P} and Rutherford, {Nicholas G} and Hadden, {Jonathan M} and John O'Reilly and Pikyee Ma and Massoud Saidijam and Patching, {Simon G} and Hope, {Ryan J} and Norbertczak, {Halina T} and Roach, {Peter C J} and So Iwata and Henderson, {Peter J F} and Cameron, {Alexander D}",

note = "Keywords: Actinomycetales; Amino Acid Sequence; Bacterial Proteins; Binding Sites; Cations; Cell Membrane; Crystallography, X-Ray; Hydantoins; Ion Transport; Models, Molecular; Molecular Sequence Data; Nucleobase Transport Proteins; Protein Conformation; Protein Structure, Secondary; Sodium; Symporters",

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doi = "10.1126/science.1164440",

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AU - Weyand, Simone

AU - Shimamura, Tatsuro

AU - Yajima, Shunsuke

AU - Suzuki, Shun'ichi

AU - Mirza, Osman Asghar

AU - Krusong, Kuakarun

AU - Carpenter, Elisabeth P

AU - Rutherford, Nicholas G

AU - Hadden, Jonathan M

AU - O'Reilly, John

AU - Ma, Pikyee

AU - Saidijam, Massoud

AU - Patching, Simon G

AU - Hope, Ryan J

AU - Norbertczak, Halina T

AU - Roach, Peter C J

AU - Iwata, So

AU - Henderson, Peter J F

AU - Cameron, Alexander D

N1 - Keywords: Actinomycetales; Amino Acid Sequence; Bacterial Proteins; Binding Sites; Cations; Cell Membrane; Crystallography, X-Ray; Hydantoins; Ion Transport; Models, Molecular; Molecular Sequence Data; Nucleobase Transport Proteins; Protein Conformation; Protein Structure, Secondary; Sodium; Symporters

PY - 2008

Y1 - 2008

N2 - The nucleobase-cation-symport-1 (NCS1) transporters are essential components of salvage pathways for nucleobases and related metabolites. Here, we report the 2.85-angstrom resolution structure of the NCS1 benzyl-hydantoin transporter, Mhp1, from Microbacterium liquefaciens. Mhp1 contains 12 transmembrane helices, 10 of which are arranged in two inverted repeats of five helices. The structures of the outward-facing open and substrate-bound occluded conformations were solved, showing how the outward-facing cavity closes upon binding of substrate. Comparisons with the leucine transporter LeuT(Aa) and the galactose transporter vSGLT reveal that the outward- and inward-facing cavities are symmetrically arranged on opposite sides of the membrane. The reciprocal opening and closing of these cavities is synchronized by the inverted repeat helices 3 and 8, providing the structural basis of the alternating access model for membrane transport.

AB - The nucleobase-cation-symport-1 (NCS1) transporters are essential components of salvage pathways for nucleobases and related metabolites. Here, we report the 2.85-angstrom resolution structure of the NCS1 benzyl-hydantoin transporter, Mhp1, from Microbacterium liquefaciens. Mhp1 contains 12 transmembrane helices, 10 of which are arranged in two inverted repeats of five helices. The structures of the outward-facing open and substrate-bound occluded conformations were solved, showing how the outward-facing cavity closes upon binding of substrate. Comparisons with the leucine transporter LeuT(Aa) and the galactose transporter vSGLT reveal that the outward- and inward-facing cavities are symmetrically arranged on opposite sides of the membrane. The reciprocal opening and closing of these cavities is synchronized by the inverted repeat helices 3 and 8, providing the structural basis of the alternating access model for membrane transport.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1126/science.1164440

DO - 10.1126/science.1164440

M3 - Journal article

C2 - 18927357

SN - 0036-8075

VL - 322

SP - 709

EP - 713

JO - Science

JF - Science

IS - 5902

ER -

Structure and molecular mechanism of a nucleobase-cation-symport-1 family transporter

Abstract

Keywords

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