Identification of small‐molecule binding sites of a ubiquitin‐conjugating enzyme‐UBE2T through fragment‐based screening

Identification of small‐molecule binding sites of a ubiquitin‐conjugating enzyme‐UBE2T through fragment‐based screening

Protein Science

10.1002/pro.4904

http://dx.doi.org/10.1002/pro.4904

Yong Yao Loh, Jothi Anantharajan, Qiwei Huang, Weijun Xu, Justina Fulwood, Hui Qi Ng, Elizabeth Yihui Ng, Chong Yu Gea, Meng Ling Choong, Qian Wen Tan, Xiaoying Koh, Wan Hsin Lim, Kassoum Nacro, Joseph Cherian, Nithya Baburajendran, Zhiyuan Ke, CongBao Kang

15 February 2024

Loh, Y. Y., Anantharajan, J., Huang, Q., Xu, W., Fulwood, J., Ng, H. Q., Ng, E. Y., Gea, C. Y., Choong, M. L., Tan, Q. W., Koh, X., Lim, W. H., Nacro, K., Cherian, J., Baburajendran, N., Ke, Z., & Kang, C. (2024). Identification of small‐molecule binding sites of a ubiquitin‐conjugating enzyme‐UBE2T through fragment‐based screening. Protein Science, 33(3). Portico. https://doi.org/10.1002/pro.4904

AbstractUBE2T is an attractive target for drug development due to its linkage with several types of cancers. However, the druggability of ubiquitin‐conjugating E2 (UBE2T) is low because of the lack of a deep and hydrophobic pocket capable of forming strong binding interactions with drug‐like small molecules. Here, we performed fragment screening using 19F‐nuclear magnetic resonance (NMR) and validated the hits with 1H‐15N‐heteronuclear single quantum coherence (HSQC) experiment and X‐ray crystallographic studies. The cocrystal structures obtained revealed the binding modes of the hit fragments and allowed for the characterization of the fragment‐binding sites. Further screening of structural analogues resulted in the identification of a compound series with inhibitory effect on UBE2T activity. Our current study has identified two new binding pockets in UBE2T, which will be useful for the development of small molecules to regulate the function of this protein. In addition, the compounds identified in this study can serve as chemical starting points for the development of UBE2T modulators.

Publisher Copyright

This research is supported by core funding from: Experimental Drug Development Centre (EDDC)
Grant Reference no. : N. A.

This is the peer reviewed version of the following article: Loh, Y. Y., Anantharajan, J., Huang, Q., Xu, W., Fulwood, J., Ng, H. Q., Ng, E. Y., Gea, C. Y., Choong, M. L., Tan, Q. W., Koh, X., Lim, W. H., Nacro, K., Cherian, J., Baburajendran, N., Ke, Z., & Kang, C. (2024). Identification of small‐molecule binding sites of a ubiquitin‐conjugating enzyme‐UBE2T through fragment‐based screening. Protein Science, 33(3). Portico. https://doi.org/10.1002/pro.4904 , which has been published in final form at doi.org/10.1002/pro.4904. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited."

https://oar.a-star.edu.sg/communities-collections/articles/19739

1469-896X
0961-8368

Experimental Drug Development Centre