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13 items found (0 items not approved), displaying 1 to 10.[First/Prev] 1, 2 [Next/Last]

Instruments / Technical Area	Publication Details	Published
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography	Single-domain antibodies as crystallization chaperones to enable structure-based inhibitor development for RBR E3 ubiquitin ligases Yi-chun Isabella Tsai , Henrik Johansson , David Dixon , Stephen Martin , Chun-wa Chung , Jane Clarkson , David House , Katrin Rittinger Cell Chemical Biology DOI: 10.1016/j.chembiol.2019.11.007 Diamond Proposal Number(s): [18566] Open Access Show Abstract ▼ Abstract: Protein ubiquitination plays a key role in the regulation of cellular processes, and misregulation of the ubiquitin system is linked to many diseases. So far, development of tool compounds that target enzymes of the ubiquitin system has been slow and only a few specific inhibitors are available. Here, we report the selection of single-domain antibodies (single-dAbs) based on a human scaffold that recognize the catalytic domain of HOIP, a subunit of the multi-component E3 LUBAC and member of the RBR family of E3 ligases. Some of these dAbs affect ligase activity and provide mechanistic insight into the ubiquitin transfer mechanism of different E2-conjugating enzymes. Furthermore, we show that the co-crystal structure of a HOIP RBR/dAb complex serves as a robust platform for soaking of ligands that target the active site cysteine of HOIP, thereby providing easy access to structure-based ligand design for this important class of E3 ligases.	Dec 2019
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	Differences in the conformational energy landscape of CDK1 and CDK2 suggest a mechanism for achieving selective CDK inhibition Daniel J. Wood , Svitlana Korolchuk , Natalie J. Tatum , Lan-zhen Wang , Jane A. Endicott , Martin E. M. Noble , Mathew P. Martin Cell Chemical Biology DOI: 10.1016/j.chembiol.2018.10.015 Diamond Proposal Number(s): [18598, 13587] Open Access Show Abstract ▼ Abstract: Dysregulation of the cell cycle characterizes many cancer subtypes, providing a rationale for developing cyclin-dependent kinase (CDK) inhibitors. Potent CDK2 inhibitors might target certain cancers in which CCNE1 is amplified. However, current CDK2 inhibitors also inhibit CDK1, generating a toxicity liability. We have used biophysical measurements and X-ray crystallography to investigate the ATP-competitive inhibitor binding properties of cyclin-free and cyclin-bound CDK1 and CDK2. We show that these kinases can readily be distinguished by such inhibitors when cyclin-free, but not when cyclin-bound. The basis for this discrimination is unclear from either inspection or molecular dynamics simulation of ligand-bound CDKs, but is reflected in the contacts made between the kinase N- and C-lobes. We conclude that there is a subtle but profound difference between the conformational energy landscapes of cyclin-free CDK1 and CDK2. The unusual properties of CDK1 might be exploited to differentiate CDK1 from other CDKs in future cancer therapeutic design.	Nov 2018
I03-Macromolecular Crystallography I04-1-Macromolecular Crystallography (fixed wavelength) I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	(ADP-ribosyl)hydrolases: structural basis for differential substrate recognition and inhibition Johannes Gregor Matthias Rack , Antonio Ariza , Bryon S. Drown , Callum Henfrey , Edward Bartlett , Tomohiro Shirai , Paul J. Hergenrother , Ivan Ahel Cell Chemical Biology DOI: 10.1016/j.chembiol.2018.11.001 Diamond Proposal Number(s): [18069] Open Access Show Abstract ▼ Abstract: Protein ADP-ribosylation is a highly dynamic post-translational modification. The rapid turnover is achieved, among others, by ADP-(ribosyl)hydrolases (ARHs), an ancient family of enzymes that reverses this modification. Recently ARHs came into focus due to their role as regulators of cellular stresses and tumor suppressors. Here we present a comprehensive structural analysis of the enzymatically active family members ARH1 and ARH3. These two enzymes have very distinct substrate requirements. Our data show that binding of the adenosine ribose moiety is highly diverged between the two enzymes, whereas the active sites harboring the distal ribose closely resemble each other. Despite this apparent similarity, we elucidate the structural basis for the selective inhibition of ARH3 by the ADP-ribose analogues ADP-HPD and arginine-ADP-ribose. Together, our biochemical and structural work provides important insights into the mode of enzyme-ligand interaction, helps to understand differences in their catalytic behavior, and provides useful tools for targeted drug design.	Nov 2018
I04-1-Macromolecular Crystallography (fixed wavelength) I24-Microfocus Macromolecular Crystallography	A potent and selective PARP11 inhibitor suggests coupling between cellular localization and catalytic activity Ilsa T. Kirby , Ana Kojic , Moriah R. Arnold , Ann-gerd Thorsell , Tobias Karlberg , Anke Vermehren-schmaedick , Raashi Sreenivasan , Carsten Schultz , Herwig Schüler , Michael S. Cohen Cell Chemical Biology DOI: 10.1016/j.chembiol.2018.09.011 Show Abstract ▼ Abstract: Poly-ADP-ribose polymerases (PARPs1-16) play pivotal roles in diverse cellular processes. PARPs that catalyze poly-ADP-ribosylation (PARylation) are the best characterized PARP family members because of the availability of potent and selective inhibitors for these PARPs. There has been comparatively little success in developing selective small-molecule inhibitors of PARPs that catalyze mono-ADP-ribosylation (MARylation), limiting our understanding of the cellular role of MARylation. Here we describe the structure-guided design of inhibitors of PARPs that catalyze MARylation. The most selective analog, ITK7, potently inhibits the MARylation activity of PARP11, a nuclear envelope-localized PARP. ITK7 is greater than 200-fold selective over other PARP family members. Using live-cell imaging, we show that ITK7 causes PARP11 to dissociate from the nuclear envelope. These results suggest that the cellular localization of PARP11 is regulated by its catalytic activity.	Oct 2018
I04-1-Macromolecular Crystallography (fixed wavelength)	Construction of fluorescent analogs to follow the uptake and distribution of cobalamin (vitamin B12) in bacteria, worms, and plants Andrew D. Lawrence , Emi Nemoto-smith , Evelyne Deery , Joseph A. Baker , Susanne Schroeder , David G. Brown , Jennifer M. A. Tullet , Mark J. Howard , Ian R. Brown , Alison G. Smith , Helena I. Boshoff , Clifton E. Barry , Martin J. Warren Cell Chemical Biology DOI: 10.1016/j.chembiol.2018.04.012 Show Abstract ▼ Abstract: Vitamin B12 is made by only certain prokaryotes yet is required by a number of eukaryotes such as mammals, fish, birds, worms, and Protista, including algae. There is still much to learn about how this nutrient is trafficked across the domains of life. Herein, we describe ways to make a number of different corrin analogs with fluorescent groups attached to the main tetrapyrrole-derived ring. A further range of analogs were also constructed by attaching similar fluorescent groups to the ribose ring of cobalamin, thereby generating a range of complete and incomplete corrinoids to follow uptake in bacteria, worms, and plants. By using these fluorescent derivatives we were able to demonstrate that Mycobacterium tuberculosis is able to acquire both cobyric acid and cobalamin analogs, that Caenorhabditis elegans takes up only the complete corrinoid, and that seedlings of higher plants such as Lepidium sativum are also able to transport B12.	May 2018
I03-Macromolecular Crystallography	Structure of the Guanidine III Riboswitch David Lilley , Lin Huang , Jia Wang , Timothy J. Wilson Cell Chemical Biology DOI: 10.1016/j.chembiol.2017.08.021 Diamond Proposal Number(s): [14980] Open Access Show Abstract ▼ Abstract: Riboswitches are structural elements found in mRNA molecules that couple small-molecule binding to regulation of gene expression, usually by controlling transcription or translation. We have determined high-resolution crystal structures of the ykkC guanidine III riboswitch from Thermobifida fusca. The riboswitch forms a classic H-type pseudoknot that includes a triple helix that is continuous with a central core of conserved nucleotides. These form a left-handed helical ramp of inter-nucleotide interactions, generating the guanidinium cation binding site. The ligand is hydrogen bonded to the Hoogsteen edges of two guanine bases. The binding pocket has a side opening that can accommodate a small side chain, shown by structures with bound methylguanidine, aminoguanidine, ethylguanidine, and agmatine. Comparison of the new structure with those of the guanidine I and II riboswitches reveals that evolution generated three different structural solutions for guanidine binding and subsequent gene regulation, although with some common elements.	Oct 2017
I02-Macromolecular Crystallography	General and Modular Strategy for Designing Potent, Selective, and Pharmacologically Compliant Inhibitors of Rhomboid Proteases Anežka Tichá , Stancho Stanchev , Kutti R. Vinothkumar , David C. Mikles , Petr Pachl , Jakub Began , Jan Škerle , Kateřina Švehlová , Minh T.n. Nguyen , Steven H.l. Verhelst , Darren C. Johnson , Daniel A. Bachovchin , Martin Lepšík , Pavel Majer , Kvido Strisovsky Cell Chemical Biology DOI: 10.1016/j.chembiol.2017.09.007 Open Access Show Abstract ▼ Abstract: Rhomboid-family intramembrane proteases regulate important biological processes and have been associated with malaria, cancer, and Parkinson's disease. However, due to the lack of potent, selective, and pharmacologically compliant inhibitors, the wide therapeutic potential of rhomboids is currently untapped. Here, we bridge this gap by discovering that peptidyl α-ketoamides substituted at the ketoamide nitrogen by hydrophobic groups are potent rhomboid inhibitors active in the nanomolar range, surpassing the currently used rhomboid inhibitors by up to three orders of magnitude. Such peptidyl ketoamides show selectivity for rhomboids, leaving most human serine hydrolases unaffected. Crystal structures show that these compounds bind the active site of rhomboid covalently and in a substrate-like manner, and kinetic analysis reveals their reversible, slow-binding, non-competitive mechanism. Since ketoamides are clinically used pharmacophores, our findings uncover a straightforward modular way for the design of specific inhibitors of rhomboid proteases, which can be widely applicable in cell biology and drug discovery.	Oct 2017
	Iron Biochemistry is Correlated with Amyloid Plaque Morphology in an Established Mouse Model of Alzheimer's Disease Neil D. Telling , James Everett , Joanna F. Collingwood , Jon Dobson , Gerrit Van Der Laan , Joseph J. Gallagher , Jian Wang , Adam P. Hitchcock Cell Chemical Biology DOI: 10.1016/j.chembiol.2017.07.014 Show Abstract ▼ Abstract: A signature characteristic of Alzheimer’s disease (AD) is aggregation of amyloid-beta (Ab) fibrils in the brain. Nevertheless, the links between Ab and AD pathology remain incompletely understood. It has been proposed that neurotoxicity arising from aggregation of the Ab1-42 peptide can in part be explained by metal ion binding interactions. Using advanced X-ray microscopy techniques at submicron resolution, we investigated relationships between iron biochemistry and AD pathology in intact cortex from an established mouse model over-producing Ab. We found a direct correlation of amyloid plaque morphology with iron, and evidence for the formation of an iron-amyloid complex. We also show that iron biomineral deposits in the cortical tissue contain the mineral magnetite, and provide evidence that Ab-induced chemical reduction of iron could occur in vivo. Our observations point to the specific role of iron in amyloid deposition and AD pathology, and may impact development of iron-modifying therapeutics for AD.	Sep 2017
I04-1-Macromolecular Crystallography (fixed wavelength)	A Linear Diubiquitin-Based Probe for Efficient and Selective Detection of the Deubiquitinating Enzyme OTULIN Aurelia Weber , Paul R. Elliott , Adan Pinto-fernandez , Sarah Bonham , Benedikt M. Kessler , David Komander , Farid El Oualid , Daniel Krappmann Cell Chemical Biology DOI: 10.1016/j.chembiol.2017.08.006 Diamond Proposal Number(s): [15916] Open Access Show Abstract ▼ Abstract: The methionine 1 (M1)-specific deubiquitinase (DUB) OTULIN acts as a negative regulator of nuclear factor κB signaling and immune homeostasis. By replacing Gly76 in distal ubiquitin (Ub) by dehydroalanine we designed the diubiquitin (diUb) activity-based probe UbG76Dha-Ub (OTULIN activity-based probe [ABP]) that couples to the catalytic site of OTULIN and thereby captures OTULIN in its active conformation. The OTULIN ABP displays high selectivity for OTULIN and does not label other M1-cleaving DUBs, including CYLD. The only detectable cross-reactivities were the labeling of USP5 (Isopeptidase T) and an ATP-dependent assembly of polyOTULIN ABP chains via Ub-activating E1 enzymes. Both cross-reactivities were abolished by the removal of the C-terminal Gly in the ABP's proximal Ub, yielding the specific OTULIN probe UbG76Dha-UbΔG76 (OTULIN ABPΔG76). Pull-downs demonstrate that substrate-bound OTULIN associates with the linear ubiquitin chain assembly complex (LUBAC). Thus, we present a highly selective ABP for OTULIN that will facilitate studying the cellular function of this essential DUB.	Sep 2017
I04-Macromolecular Crystallography I24-Microfocus Macromolecular Crystallography	The Structure of the Guanidine-II Riboswitch Lin Huang , Jia Wang , David M. J. Lilley Cell Chemical Biology DOI: 10.1016/j.chembiol.2017.05.014 Diamond Proposal Number(s): [14980] Open Access Show Abstract ▼ Abstract: The guanidine-II (mini-ykkC) riboswitch is the smallest of the guanidine-responsive riboswitches, comprising two stem loops of similar sequence. We have solved high-resolution crystal structures of both stem loops for the riboswitch from Gloeobacter violaceus. The stem loops have a strong propensity to dimerize by intimate loop-loop interaction. The dimerization creates specific binding pockets for two guanidine molecules, explaining their cooperative binding. Within the binding pockets the ligands are hydrogen bonded to a guanine at O6 and N7, and to successive backbone phosphates. Additionally they are each stacked upon a guanine nucleobase. One side of the pocket has an opening to the solvent, slightly lowering the specificity of ligand binding, and structures with bound methylguanidine, aminoguanidine, and agmatine show how this is possible.	May 2017

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