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Instruments / Technical Area	Publication Details	Published	Actions
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	DELTEX2 C-terminal domain recognizes and recruits ADP-ribosylated proteins for ubiquitination Syed Feroj Ahmed , Lori Buetow , Mads Gabrielsen , Sergio Lilla , Chatrin Chatrin , Gary J. Sibbet , Sara Zanivan , Danny Huang Science Advances 6 DOI: 10.1126/sciadv.abc0629 Diamond Proposal Number(s): [16258] Open Access Show Abstract ▼ Abstract: Cross-talk between ubiquitination and ADP-ribosylation regulates spatiotemporal recruitment of key players in many signaling pathways. The DELTEX family ubiquitin ligases (DTX1 to DTX4 and DTX3L) are characterized by a RING domain followed by a C-terminal domain (DTC) of hitherto unknown function. Here, we use two label-free mass spectrometry techniques to investigate the interactome and ubiquitinated substrates of human DTX2 and identify a large proportion of proteins associated with the DNA damage repair pathway. We show that DTX2-catalyzed ubiquitination of these interacting proteins requires PARP1/2-mediated ADP-ribosylation and depends on the DTC domain. Using a combination of structural, biochemical, and cell-based techniques, we show that the DTX2 DTC domain harbors an ADP-ribose–binding pocket and recruits poly-ADP-ribose (PAR)–modified proteins for ubiquitination. This PAR-binding property of DTC domain is conserved across the DELTEX family E3s. These findings uncover a new ADP-ribose–binding domain that facilitates PAR-dependent ubiquitination.	Aug 2020
I02-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Discovery of potent and selective MRCK inhibitors with therapeutic effect on skin cancer Mathieu Unbekandt , Simone Belshaw , Justin Bower , Maeve Clarke , Jacqueline Cordes , Diane Crighton , Daniel R. Croft , Martin J. Drysdale , Mathew J. Garnett , Kathryn Gill , Christopher Gray , David A. Greenhalgh , James A. M. Hall , Jennifer Konczal , Sergio Lilla , Duncan Mcarthur , Patricia Mcconnell , Laura Mcdonald , Lynn Mcgarry , Heather Mckinnon , Carol Mcmenemy , Mokdad Mezna , Nicholas A. Morrice , June Munro , Gregory Naylor , Nicola Rath , Alexander W. Schüttelkopf , Mairi Sime , Michael F. Olson Cancer Research DOI: 10.1158/0008-5472.CAN-17-2870 Diamond Proposal Number(s): [8659] Show Abstract ▼ Abstract: The myotonic dystrophy-related Cdc42-binding kinases MRCKα and MRCKβ contribute to the regulation of actin-myosin cytoskeleton organization and dynamics, acting in concert with the Rho-associated coiled-coil kinases ROCK1 and ROCK2. The absence of highly potent and selective MRCK inhibitors has resulted in relatively little knowledge of the potential roles of these kinases in cancer. Here we report the discovery of the azaindole compounds BDP8900 and BDP9066 as potent and selective MRCK inhibitors that reduce substrate phosphorylation, leading to morphological changes in cancer cells along with inhibition of their motility and invasive character. In over 750 human cancer cell lines tested, BDP8900 and BDP9066 displayed consistent anti-proliferative effects with greatest activity in hematological cancer cells. Mass spectrometry identified MRCKα S1003 as an autophosphorylation site, enabling development of a phosphorylation-sensitive antibody tool to report on MRCKα status in tumor specimens. In a two-stage chemical carcinogenesis model of murine squamous cell carcinoma, topical treatments reduced MRCKα S1003 autophosphorylation and skin papilloma outgrowth. In parallel work, we validated a phospho-selective antibody with the capability to monitor drug pharmacodynamics. Taken together, our findings establish an important oncogenic role for MRCK in cancer, and they offer an initial preclinical proof of concept for MRCK inhibition as a valid therapeutic strategy.	Jan 2018

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