PT  - JOURNAL ARTICLE
AU  - Yang Yang
AU  - Yibo Zhu
AU  - Tao Yang
AU  - Tao Li
AU  - Yuan Ju
AU  - Yingjie Song
AU  - Jun He
AU  - Huanxiang Liu
AU  - Rui Bao
AU  - Youfu Luo
TI  - Inhibiting <em>Mycobacterium tuberculosis</em> ClpP1P2 by addressing the equatorial handle domain of ClpP1 subunit
AID  - 10.1101/713214
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 713214
4099  - http://biorxiv.org/content/early/2019/07/24/713214.short
4100  - http://biorxiv.org/content/early/2019/07/24/713214.full
AB  - Unlike other bacterial ClpP systems, mycobacterial ClpP1P2 complex is essential for mycobacterial survival. The functional details of Mycobacterium tuberculosis (Mtb) ClpP1P2 remains largely elusive and selectively targeting ClpP of different species is a big challenge. In this work, cediranib was demonstrated to significantly decrease the activity of MtbClpP1P2. By solving the crystal structure of cediranib-bound MtbClpP1P2, we found that cediranib dysregulates MtbClpP1P2 by interfering with handle domain of the equatorial region of MtbClpP1, indicating that the inter-ring dynamics are crucial for its function. This finding provides direct evidence for the notion that a conformational switch in the equatorial handle domain is essential for ClpP activity. We also present biochemical data to interpret the distinct interaction pattern and inhibitory properties of cediranib toward MtbClpP1P2. These results suggest that the variable handle domain region is responsible for the species-selectivity of cediranib, which suggests the equatorial handle domain as a potential region for screening pathogen-specific ClpP inhibitors.