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Structure-based design of a pathway-specific nuclear import inhibitor

Abstract

Kapβ2 (also called transportin) recognizes PY nuclear localization signal (NLS), a new class of NLS with a R/H/Kx(2–5)PY motif. Here we show that Kapβ2 complexes containing hydrophobic and basic PY-NLSs, as classified by the composition of an additional N-terminal motif, converge in structure only at consensus motifs, which explains ligand diversity. On the basis of these data and complementary biochemical analyses, we designed a Kapβ2-specific nuclear import inhibitor, M9M.

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Figure 1: Kapβ2 bound to bPY-NLS of hnRNP M.
Figure 2: M9M in vitro and in vivo inhibition studies.

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Acknowledgements

We thank the University of Texas Southwestern's Structural Biology Laboratory, C. Thomas, N. Satterly, M. Matunis, M. Swanson, H. Yu, E. Seto and R. Bassel-Duby. The US Department of Energy, Offices of Science and Basic Energy Sciences (contract W-31-109-ENG-38) supported Advanced Photon Source use. Y.M.C. is funded by US National Institutes of Health grant R01-GM069909, Welch Foundation grant I-1532 and the University of Texas Southwestern Endowed Scholars Program, B.M.A.F. by US National Institutes of Health grant R01-GM067159-01.

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Correspondence to Yuh Min Chook.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Interactions between hnRNP M-NLS and Kapβ2. (PDF 1318 kb)

Supplementary Fig. 2

Isothermal titration calorimetry measurements. (PDF 499 kb)

Supplementary Fig. 3

Competition isothermal titration calorimetry data for inhibitor. (PDF 279 kb)

Supplementary Fig. 4

M9M, hnRNP M-NLS and hnRNP A1-NLS bind the same site on Kapβ2. (PDF 469 kb)

Supplementary Fig. 5

Western blots using antibodies against hnRNPs A1 and M. (PDF 899 kb)

Supplementary Table 1

Data collection and refinement statistics. (PDF 194 kb)

Supplementary Table 2

Kd measurements using isothermal titration calorimetry. (PDF 69 kb)

Supplementary Methods (PDF 175 kb)

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Cansizoglu, A., Lee, B., Zhang, Z. et al. Structure-based design of a pathway-specific nuclear import inhibitor. Nat Struct Mol Biol 14, 452–454 (2007). https://doi.org/10.1038/nsmb1229

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