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The structure of a small GTPaseRhoA in complex with PDZRhoGEF and the inhibitor HL47

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Abstract

Objectives

To study the structure of a small GTPaseRhoA in complex with PDZRhoGEF and the inhibitor HL47, and to provide an easier template for R&D of RhoA inhibitor.

Results

Our initial attempts to obtain a binary complex of RhoA with the inhibitor HL47 were unsuccessful probably due to the presence of GDP. By targeting a ternary complex involving the RhoA-specific guanine nucleotide exchange factor PDZRhoGEF, we eliminated GDP and obtained a 2.3 Å structure of the RhoA-PDZRhoGEF-inhibitor HL47 ternary complex.

Conclusion

This structure provides a new template for target-based pharmaceutical design against RhoA.

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Acknowledgements

The authors gratefully acknowledge financial support from the National Natural Science Foundation of China (Grant Nos. 81202394, 21222211, 21372001 and 91313303), the Ministry of Education of China’s Program for New Century Excellent Talents in University (Grant No. NCET-12-0853), the Young Medical Talents Project of Jiangsu Province, and the Applied Basic Research Programs of Suzhou Sci-tech Bureau, China (Grant No. SYS201219).

Supporting information

Supplementary Table 1—Macromolecule production data for RhoA and PDZRhoGEF.

Supplementary Table 2—Crystallization information.

Supplementary Table 3—Data collection and processing.

Supplementary Table 4—Structure refinement.

Author information

Author notes

    Authors and Affiliations

    1. Department of Clinical Pharmacology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, People’s Republic of China

      Zhaowei Yan, Sheng Ma, Yan Zhang & Liyan Miao

    2. Wuxi Biortus Biosciences Co.Ltd, Jiangyin, Jiangsu, 214437, People’s Republic of China

      La Ma & Feng Wang

    3. Shanghai Key Laboratory of New Drug Design, School of Pharmacy East China University of Science and Technology, Shanghai, 200237, People’s Republic of China

      Jian Li

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    1. Zhaowei Yan
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    2. Sheng Ma
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    3. Yan Zhang
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    5. Feng Wang
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    Corresponding authors

    Correspondence to Jian Li or Liyan Miao.

    Additional information

    Zhaowei Yan and Sheng Ma have contributed equally to this work.

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    Yan, Z., Ma, S., Zhang, Y. et al. The structure of a small GTPaseRhoA in complex with PDZRhoGEF and the inhibitor HL47. Biotechnol Lett 39, 745–750 (2017). https://doi.org/10.1007/s10529-017-2292-7

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    • DOI: https://doi.org/10.1007/s10529-017-2292-7

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