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Structural Basis for Phototoxicity of the Genetically Encoded Photosensitizer KillerRed

  1. Author:
    Pletnev, S.
    Gurskaya, N. G.
    Pletneva, N. V.
    Lukyanov, K. A.
    Chudakov, D. M.
    Martynov, V. I.
    Popov, V. O.
    Kovalchuk, M. V.
    Wlodawer, A.
    Dauter, Z.
    Pletnev, V.

  2. Author Address

    Dauter, Zbigniew] NCI, Synchrotron Radiat Res Sect, Macromol Crystallog Lab, SAIC Frederick Inc, Argonne, IL 60439 USA. [Gurskaya, Nadya G.; Pletneva, Nadya V.; Lukyanov, Konstantin A.; Chudakov, Dmitri M.; Martynov, Vladimir I.; Pletnev, Vladimir] Russian Acad Sci, Shemyakin Ovchinnikov Inst Bioorgan Chem, Moscow 117997, Russia. [Popov, Vladimir O.] Russian Acad Sci, AN Bach Inst Biochem, Moscow 117234, Russia. [Kovalchuk, Mikhail V.] Russian Acad Sci, Inst Crystallog, Moscow 119333, Russia. [Wlodawer, Alexander] NCI, Prot Struct Sect, Macromol Crystallog Lab, NIH, Frederick, MD 21702 USA.
    1. Year: 2009
  2. Journal: Journal of Biological Chemistry
    1. 284
    2. 46
    3. Pages: 32028-32039
  4. Type of Article: Article
  1. Abstract:

    KillerRed is the only known fluorescent protein that demonstrates notable phototoxicity, exceeding that of the other green and red fluorescent proteins by at least 1,000-fold. KillerRed could serve as an instrument to inactivate target proteins or to kill cell populations in photodynamic therapy. However, the nature of KillerRed phototoxicity has remained unclear, impeding the development of more phototoxic variants. Here we present the results of a high resolution crystallographic study of KillerRed in the active fluorescent and in the photobleached non-fluorescent states. A unique and striking feature of the structure is a water-filled channel reaching the chromophore area from the end cap of the beta-barrel that is probably one of the key structural features responsible for phototoxicity. A study of the structure-function relationship of KillerRed, supported by structure-based, site-directed mutagenesis, has also revealed the key residues most likely responsible for the phototoxic effect. In particular, Glu(68) and Ser(119), located adjacent to the chromophore, have been assigned as the primary trigger of the reaction chain.

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  2. DOI: 10.1074/jbc.M109.054973
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