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Instruments / Technical Area	Publication Details	Published
B21-High Throughput SAXS I03-Macromolecular Crystallography	The mechanism of allosteric activation of SYK kinase derived from multiple phospho-ITAM-bound structures William Bradshaw , Gemma Harris , Opher Gileadi , Vittorio Katis Structure 10 DOI: 10.1016/j.str.2024.09.024 Diamond Proposal Number(s): [19301, 28172, 34598] Open Access Show Abstract ▼ Abstract: Spleen tyrosine kinase (SYK) is central to adaptive and innate immune signaling. It features a regulatory region containing tandem SH2 (tSH2) domains separated by a helical “hinge” segment keeping SYK inactive by associating with the kinase domain. SYK activation is triggered when the tSH2 domains bind to a phosphorylated immunoreceptor tyrosine-based activation motif (ITAM) found on receptor tails. Past mutational studies have indicated that ITAM binding disrupts the hinge-kinase interaction, leading to SYK phosphorylation and activation. However, the mechanism of this process is unclear, as the ITAM interaction occurs far from the hinge region. We have determined crystal structures of three phospho-ITAMs in complex with the tSH2 domains, revealing a highly conserved binding mechanism. These structures, together with mutational studies and biophysical analyses, reveal that phospho-ITAM binding restricts SH2 domain movement and causes allosteric changes in the hinge region. These changes are not compatible with the association of the kinase domain, leading to kinase activation.	Oct 2024
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Regulation of inositol 5-phosphatase activity by the C2 domain of SHIP1 and SHIP2 William J. Bradshaw , Emma C. Kennedy , Tiago Moreira , Luke A. Smith , Rod Chalk , Vittorio L. Katis , Justin L. P. Benesch , Paul E. Brennan , Emma J. Murphy , Opher Gileadi Structure 44 DOI: 10.1016/j.str.2024.01.005 Diamond Proposal Number(s): [22717, 15433, 19301] Open Access Show Abstract ▼ Abstract: SHIP1, an inositol 5-phosphatase, plays a central role in cellular signaling. As such, it has been implicated in many conditions. Exploiting SHIP1 as a drug target will require structural knowledge and the design of selective small molecules. We have determined apo, and magnesium and phosphate-bound structures of the phosphatase and C2 domains of SHIP1. The C2 domains of SHIP1 and the related SHIP2 modulate the activity of the phosphatase domain. To understand the mechanism, we performed activity assays, hydrogen-deuterium exchange mass spectrometry, and molecular dynamics on SHIP1 and SHIP2. Our findings demonstrate that the influence of the C2 domain is more pronounced for SHIP2 than SHIP1. We determined 91 structures of SHIP1 with fragments bound, with some near the interface between the two domains. We performed a mass spectrometry screen and determined four structures with covalent fragments. These structures could act as starting points for the development of potent, selective probes.	Feb 2024
I03-Macromolecular Crystallography I04-Macromolecular Crystallography	Discovery of FERM domain protein-protein interaction inhibitors for MSN and CD44 as a potential therapeutic approach for Alzheimer’s disease Yuhong Du , William J. Bradshaw , Tina M. Leisner , Joel K. Annor-Gyamfi , Kun Qian , Frances M. Bashore , Arunima Sikdar , Felix O. Nwogbo , Andrey A. Ivanov , Stephen V. Frye , Opher Gileadi , Paul E. Brennan , Allan I. Levey , Alison D. Axtman , Kenneth H. Pearce , Haian Fu , Vittorio L. Katis , Ishita Ajith , Jeff Aube , Ranjita S. Betarbet , Juan Botas , Peter J. Brown , Robert R. Butler , Jacob L. Capener , Gregory W. Carter , Gregory A. Cary , Catherine Chen , Rachel Commander , Sabrina Daglish , Suzanne Doolen , Aled M. Edwards , Michelle E. Etoundi , Kevin J. Frankowski , Marta Glavatshikh , Jake Gockley , Katerina Gospodinova , Anna K. Greenwood , Peter A. Greer , Lea T. Grinberg , Shiva Guduru , Levon Halabelian , Crystal Han , Brian Hardy , Laura M. Heath , Stephanie Howell , Suman Jayadev , Stephen Keegan , May Khanna , Dmitri Kireev , Carl Laflamme , Karina Leal , Tom V. Lee , Qianjin Li , David Li-Kroeger , Zhandong Liu , Benjamin A. Logsdon , Frank M. Longo , Lara M. Mangravite , Peter S. Mcpherson , Richard M. Nwakamma , Carolyn A. Paisie , Arti Parihar , Min Qui , Stacey J. Sukoff Rizzo , Karolina A. Rygiel , Julie Schumacher , David D. Scott , Nicholas T. Seyfried , Joshua M. Shulman , Ben Siciliano , Nathaniel Smith , Michael Stashko , Judith A. Tello Vega , Dilipkumar Uredi , Dongxue Wang , Jianjun Wang , Xiaodong Wang , Zhexing Wen , Jesse C. Wiley , Alexander Wilkes , Charles A. Williams , Timothy M. Willson , Aliza Wingo , Thomas S. Wingo , Novak Yang , Jessica E. Young , Miao Yu , Elizabeth L. Zoeller Journal Of Biological Chemistry 20 DOI: 10.1016/j.jbc.2023.105382 Diamond Proposal Number(s): [19301, 19301] Open Access	Oct 2023
I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	STAG1 vulnerabilities for exploiting cohesin synthetic lethality in STAG2-deficient cancers Petra Van Der Lelij , Joseph A. Newman , Simone Lieb , Julian Jude , Vittorio Katis , Thomas Hoffmann , Matthias Hinterndorfer , Gerd Bader , Norbert Kraut , Mark A. Pearson , Jan-Michael Peters , Johannes Zuber , Opher Gileadi , Mark Petronczki Life Science Alliance 3 DOI: 10.26508/lsa.202000725 Diamond Proposal Number(s): [19301, 18145] Open Access Show Abstract ▼ Abstract: The cohesin subunit STAG2 has emerged as a recurrently inactivated tumor suppressor in human cancers. Using candidate approaches, recent studies have revealed a synthetic lethal interaction between STAG2 and its paralog STAG1. To systematically probe genetic vulnerabilities in the absence of STAG2, we have performed genome-wide CRISPR screens in isogenic cell lines and identified STAG1 as the most prominent and selective dependency of STAG2-deficient cells. Using an inducible degron system, we show that chemical genetic degradation of STAG1 protein results in the loss of sister chromatid cohesion and rapid cell death in STAG2-deficient cells, while sparing STAG2–wild-type cells. Biochemical assays and X-ray crystallography identify STAG1 regions that interact with the RAD21 subunit of the cohesin complex. STAG1 mutations that abrogate this interaction selectively compromise the viability of STAG2-deficient cells. Our work highlights the degradation of STAG1 and inhibition of its interaction with RAD21 as promising therapeutic strategies. These findings lay the groundwork for the development of STAG1-directed small molecules to exploit synthetic lethality in STAG2-mutated tumors.	May 2020

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