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Structure of the Bcr-Abl oncoprotein oligomerization domain

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Abstract

The Bcr-Abl oncoprotein is responsible for a wide range of human leukemias, including most cases of Philadelphia chromosome-positive chronic myelogenous leukemia. Oligomerization of Bcr-Abl is essential for oncogenicity. We determined the crystal structure of the N-terminal oligomerization domain of Bcr-Abl (residues 1–72 or Bcr1–72) and found a novel mode of oligomer formation. Two N-shaped monomers dimerize by swap** N-terminal helices and by forming an antiparallel coiled coil between C-terminal helices. Two dimers then stack onto each other to form a tetramer. The Bcr1–72 structure provides a basis for the design of inhibitors of Bcr-Abl transforming activity by disrupting Bcr-Abl oligomerization.

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Figure 1: Structural and functional domains of Bcr, Abl and Bcr-Abl37.
Figure 2: Extensive interactions in the dimer interface.
Figure 3: Packing of Bcr1–72 tetramers with two orthogonal views.
Figure 4: Dimer–dimer interface.

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Acknowledgements

We thank J. Pang and C. Kitidis for technical assistance; L. Gaffney for assistance in preparation of the manuscript; B. Chen, S. Johnston, A. Keating, C. Liu, J. Marszalek, J. Newman, R. Ren and M. Root for comments on manuscript; and C. Ogata for assistance at the Howard Hughes Medical Institute beamline (X4A) at the National Synchrotron Light Source (Brookhaven National Laboratory, Upton, NY). This research was funded by the National Institutes of Health and National Science Foundation, and utilized the W. M. Keck Foundation X-ray Crystallography Facility (Whitehead Institute, Cambridge, MA). X.Z. was supported by an Anna Fuller fellowship, and S.G. was supported by a Clinician Scientist Award from the NIH.

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  1. Peter S. Kim

    Present address: Merck Research Laboratories, 770 Sumneytown Pike, West Point, Pennsylvania, 19486-0004, USA

Authors and Affiliations

  1. Department of Biology, Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, 02142-1401, Massachusetts, USA

    Xun Zhao, Vladimir N. Malashkevich & Peter S. Kim

  2. Department of Biology, Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, 02142-1401, Massachusetts, USA

    Saghi Ghaffari & Harvey Lodish

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  1. Xun Zhao
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Correspondence to Peter S. Kim.

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Zhao, X., Ghaffari, S., Lodish, H. et al. Structure of the Bcr-Abl oncoprotein oligomerization domain. Nat Struct Mol Biol 9, 117–120 (2002). https://doi.org/10.1038/nsb747

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