The root of Danshen has

The root of (Danshen) has been widely used as traditional Chinese medicine for many years and shown to exhibit significant pharmacological activities for a variety of human diseases including cancers. Tanshinones, the major active components, belong to a group of an abietane-type diterpenes containing a 1,2-quinone in the C ring (). Both tanshinone I and tanshinone IIA have been shown to possess antitumor activities against several human cell lines, but display different activity and selectivity due to their structural differences. For example, tanshinone I inhibited migration and invasion of human lung adenocarcinoma cell line CL1–5 through reducing IL-8 expression, while tanshinone IIA induced cell differentiation and apoptosis. The structural differences among tanshinones could explain why the individual tanshinones have unique biological activities different from each other.
Main Text Absent, small, or homeotic disc1 (Ash1) is a histone methyltransferase that belongs to the Trithorax group (TrxG) proteins, epigenetic activators of developmental Hox genes in Drosophila. Ash1 and its mammalian homolog ASH1L catalyze mono- and dimethylation of lysine 36 of histone H3 (H3K36), producing a mark of transcriptionally active Shikonin (An et al., 2011). By this action, Ash1 antagonizes gene silencing by the Polycomb system, inhibiting trimethylation of lysine 27 on the same histone H3 by PRC2 (Klymenko and Müller, 2004, Schmitges et al., 2011, Yuan et al., 2011). Ash1/ASH1L is an evolutionarily conserved protein that comprises several functional domains including associated with SET domain (AWS), SET domain, post-SET domain (postSET), bromodomain, bromo-adjacent homology domain (BAH), and plant homeodomain finger (PHD) (An et al., 2011). The HMTase activity is conferred by the SET domain together with two adjacent cysteine-rich regions, AWS and postSET. However, Ash1/ASH1L shows weak catalytic activity on its own and adopts an autoinhibited state, as shown by previous biochemical and structural analyses (An et al., 2011). These studies demonstrated that the substrate-binding site is blocked by an auto-inhibitory (AI) loop protruding from the post-SET domain that must be reconfigured and opened to allow substrate access. However, the release mechanism of the Ash1/ASH1L autoinhibition remained unclear. The first hints to solve this riddle came from recent studies on Drosophila Ash1. It appeared that in vivo, Ash1 exists in a complex with two other proteins, Nurf55 and Mrg15 (Huang et al., 2017, Schmähling et al., 2018). Both proteins form direct interactions with Ash1, but not with each other, suggesting that Ash1 plays a scaffolding role. Strikingly, only Mrg15 was able to stimulate greatly the HMTase activity of Ash1 (Huang et al., 2017, Schmähling et al., 2018). The stimulation activity primarily resides in its MRG domain that binds Ash1 at a conserved FxLP motif near the SET domain. Notably, human MRG15 also recruits other proteins involved in chromatin-centric processes partly by binding their FxLP motifs (Xie et al., 2012), which raises the intriguing question of how MRG15 achieves specificity when recruiting various complexes. To that end, direct evidence of Mrg15-dependent activation of Ash1 had been provided. However, the molecular details of this activation mechanism remained unresolved. To address this question, Lee et al. (2019) and Hou et al. (2019) conceived structural studies on human ASH1L bound to MRG15. The resulting crystal structures provide insights into ASH1L-MRG15 specific interactions and discern the molecular mechanism that relieves ASH1L from its auto-inhibited state. The structures reveal two eye-catching features of the complex. The first one is the mode of ASH1L interaction with the MRG domain. This occurs almost exclusively through the N-terminal region preceding the ASH1L AWS and SET domains that recognizes two discrete hydrophobic surfaces on the MRG domain. As expected, one of them involves the conserved FxLP motif of ASH1L and its binding mode is highly conserved compared to other MRG-binding proteins (Kadlec et al., 2011, Xie et al., 2012). This site of interaction plays a dominant role in the complex formation. The second site of the ASH1L-MRG15 interactions seems to have less impact on the complex formation and is not strictly conserved. Using structure-guided mutagenesis, Lee et al. (2019) and Hou et al. (2019) further validated the functional importance of the residues involved in ASH1L-MRG15 binding. The combination of the interactions in both regions is likely to govern the specificity of ASH1L-MRG15 binding.