Crystal structures of the MJ1267 ATP binding cassette reveal an induced-fit effect at the ATPase active site of an ABC transporter

Nathan Karpowich, Oksana Martsinkevich, Linda Millen, Yu Ren Yuan, Peter L. Dai, Karen MacVey, Philip J. Thomas, John F. Hunt

Research output: Contribution to journalArticle

249 Citations (Scopus)

Abstract

Background: ATP binding cassette (ABC) transporters are ubiquitously distributed transmembrane solute pumps that play a causative role in numerous diseases. Previous structures have defined the fold of the ABC and established the flexibility of its α-helical subdomain. But the nature of the mechanical changes that occur at each step of the chemical ATPase cycle have not been defined. Results: Crystal structures were determined of the MJ1267 ABC from Methanococcus jannaschii in Mg-ADP-bound and nucleotide-free forms. Comparison of these structures reveals an induced-fit effect at the active site likely to be a consequence of nucleotide binding. In the Mg-ADP-bound structure, the loop following the Walker B moves toward the Walker A (P-loop) coupled to backbone conformational changes in the intervening "H-loop", which contains an invariant histidine. These changes affect the region believed to mediate intercassette interaction in the ABC transporter complex. Comparison of the Mg-ADP-bound structure of MJ1267 to the ATP-bound structure of HisP suggests that an outward rotation of the α-helical subdomain is coupled to the loss of a molecular contact between the γ-phosphate of ATP and an invariant glutamine in a segment connecting this subdomain to the core of the cassette. Conclusions: The induced-fit effect and rotation of the α-helical subdomain may play a role in controlling the nucleotide-dependent change in cassette-cassette interaction affinity believed to represent the power-stroke of ABC transporters. Outward rotation of the α-helical subdomain also likely facilitates Mg-ADP release after hydrolysis. The MJ1267 structures therefore define features of the nucleotide-dependent conformational changes that drive transmembrane transport in ABC transporters.

Original languageEnglish (US)
Pages (from-to)571-586
Number of pages16
JournalStructure
Volume9
Issue number7
DOIs
StatePublished - 2001

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ATP-Binding Cassette Transporters
Adenosine Diphosphate
Adenosine Triphosphatases
Catalytic Domain
Nucleotides
Adenosine Triphosphate
Methanocaldococcus
Glutamine
Histidine
Hydrolysis
Stroke
Phosphates

Keywords

  • ABC transporter
  • ATPase
  • Induced fit
  • Mechanochemistry
  • Protein crystallography
  • Transmembrane transport

ASJC Scopus subject areas

  • Molecular Biology
  • Structural Biology

Cite this

Karpowich, N., Martsinkevich, O., Millen, L., Yuan, Y. R., Dai, P. L., MacVey, K., ... Hunt, J. F. (2001). Crystal structures of the MJ1267 ATP binding cassette reveal an induced-fit effect at the ATPase active site of an ABC transporter. Structure, 9(7), 571-586. https://doi.org/10.1016/S0969-2126(01)00617-7

Crystal structures of the MJ1267 ATP binding cassette reveal an induced-fit effect at the ATPase active site of an ABC transporter. / Karpowich, Nathan; Martsinkevich, Oksana; Millen, Linda; Yuan, Yu Ren; Dai, Peter L.; MacVey, Karen; Thomas, Philip J.; Hunt, John F.

In: Structure, Vol. 9, No. 7, 2001, p. 571-586.

Research output: Contribution to journalArticle

Karpowich, Nathan ; Martsinkevich, Oksana ; Millen, Linda ; Yuan, Yu Ren ; Dai, Peter L. ; MacVey, Karen ; Thomas, Philip J. ; Hunt, John F. / Crystal structures of the MJ1267 ATP binding cassette reveal an induced-fit effect at the ATPase active site of an ABC transporter. In: Structure. 2001 ; Vol. 9, No. 7. pp. 571-586.
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T1 - Crystal structures of the MJ1267 ATP binding cassette reveal an induced-fit effect at the ATPase active site of an ABC transporter

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AU - Martsinkevich, Oksana

AU - Millen, Linda

AU - Yuan, Yu Ren

AU - Dai, Peter L.

AU - MacVey, Karen

AU - Thomas, Philip J.

AU - Hunt, John F.

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N2 - Background: ATP binding cassette (ABC) transporters are ubiquitously distributed transmembrane solute pumps that play a causative role in numerous diseases. Previous structures have defined the fold of the ABC and established the flexibility of its α-helical subdomain. But the nature of the mechanical changes that occur at each step of the chemical ATPase cycle have not been defined. Results: Crystal structures were determined of the MJ1267 ABC from Methanococcus jannaschii in Mg-ADP-bound and nucleotide-free forms. Comparison of these structures reveals an induced-fit effect at the active site likely to be a consequence of nucleotide binding. In the Mg-ADP-bound structure, the loop following the Walker B moves toward the Walker A (P-loop) coupled to backbone conformational changes in the intervening "H-loop", which contains an invariant histidine. These changes affect the region believed to mediate intercassette interaction in the ABC transporter complex. Comparison of the Mg-ADP-bound structure of MJ1267 to the ATP-bound structure of HisP suggests that an outward rotation of the α-helical subdomain is coupled to the loss of a molecular contact between the γ-phosphate of ATP and an invariant glutamine in a segment connecting this subdomain to the core of the cassette. Conclusions: The induced-fit effect and rotation of the α-helical subdomain may play a role in controlling the nucleotide-dependent change in cassette-cassette interaction affinity believed to represent the power-stroke of ABC transporters. Outward rotation of the α-helical subdomain also likely facilitates Mg-ADP release after hydrolysis. The MJ1267 structures therefore define features of the nucleotide-dependent conformational changes that drive transmembrane transport in ABC transporters.

AB - Background: ATP binding cassette (ABC) transporters are ubiquitously distributed transmembrane solute pumps that play a causative role in numerous diseases. Previous structures have defined the fold of the ABC and established the flexibility of its α-helical subdomain. But the nature of the mechanical changes that occur at each step of the chemical ATPase cycle have not been defined. Results: Crystal structures were determined of the MJ1267 ABC from Methanococcus jannaschii in Mg-ADP-bound and nucleotide-free forms. Comparison of these structures reveals an induced-fit effect at the active site likely to be a consequence of nucleotide binding. In the Mg-ADP-bound structure, the loop following the Walker B moves toward the Walker A (P-loop) coupled to backbone conformational changes in the intervening "H-loop", which contains an invariant histidine. These changes affect the region believed to mediate intercassette interaction in the ABC transporter complex. Comparison of the Mg-ADP-bound structure of MJ1267 to the ATP-bound structure of HisP suggests that an outward rotation of the α-helical subdomain is coupled to the loss of a molecular contact between the γ-phosphate of ATP and an invariant glutamine in a segment connecting this subdomain to the core of the cassette. Conclusions: The induced-fit effect and rotation of the α-helical subdomain may play a role in controlling the nucleotide-dependent change in cassette-cassette interaction affinity believed to represent the power-stroke of ABC transporters. Outward rotation of the α-helical subdomain also likely facilitates Mg-ADP release after hydrolysis. The MJ1267 structures therefore define features of the nucleotide-dependent conformational changes that drive transmembrane transport in ABC transporters.

KW - ABC transporter

KW - ATPase

KW - Induced fit

KW - Mechanochemistry

KW - Protein crystallography

KW - Transmembrane transport

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