Structural biology. Division of labor in transhydrogenase by alternating proton translocation and hydride transfer

Science. 2015 Jan 9;347(6218):178-81. doi: 10.1126/science.1260451.


NADPH/NADP(+) (the reduced form of NADP(+)/nicotinamide adenine dinucleotide phosphate) homeostasis is critical for countering oxidative stress in cells. Nicotinamide nucleotide transhydrogenase (TH), a membrane enzyme present in both bacteria and mitochondria, couples the proton motive force to the generation of NADPH. We present the 2.8 Å crystal structure of the transmembrane proton channel domain of TH from Thermus thermophilus and the 6.9 Å crystal structure of the entire enzyme (holo-TH). The membrane domain crystallized as a symmetric dimer, with each protomer containing a putative proton channel. The holo-TH is a highly asymmetric dimer with the NADP(H)-binding domain (dIII) in two different orientations. This unusual arrangement suggests a catalytic mechanism in which the two copies of dIII alternatively function in proton translocation and hydride transfer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Sequence
  • Crystallography, X-Ray
  • Molecular Sequence Data
  • NADP Transhydrogenases / chemistry*
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Protons*
  • Thermus thermophilus / enzymology


  • Protons
  • NADP Transhydrogenases

Associated data

  • PDB/4O93
  • PDB/4O9U