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Article ; Online: Weaponizing the proteasome to overcome antimalarial drug resistance.

Xiao, Zhangping / Gray, Janine L / Tate, Edward W

Cell chemical biology

2023 Volume 30, Issue 5, Page(s) 415–417

Abstract: In this issue of Cell Chemical Biology, Zhan et al. report dual-pharmacophore molecules ("artezomibs"), combining an artemisinin and proteasome inhibitor that exhibit potent activity against both wild-type and drug-resistant malarial parasites. ...

Abstract	In this issue of Cell Chemical Biology, Zhan et al. report dual-pharmacophore molecules ("artezomibs"), combining an artemisinin and proteasome inhibitor that exhibit potent activity against both wild-type and drug-resistant malarial parasites.
MeSH term(s)	Antimalarials/chemistry ; Proteasome Endopeptidase Complex ; Drug Resistance ; Proteasome Inhibitors/pharmacology ; Proteasome Inhibitors/chemistry
Chemical Substances	Antimalarials ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; Proteasome Inhibitors
Language	English
Publishing date	2023-05-17
Publishing country	United States
Document type	Journal Article ; Comment
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2023.04.012
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Article ; Online: Proteome-wide structural analysis identifies warhead- and coverage-specific biases in cysteine-focused chemoproteomics.

White, Matthew E H / Gil, Jesús / Tate, Edward W

Cell chemical biology

2023 Volume 30, Issue 7, Page(s) 828–838.e4

Abstract: Covalent drug discovery has undergone a resurgence over the past two decades and reactive cysteine profiling has emerged in parallel as a platform for ligand discovery through on- and off-target profiling; however, the scope of this approach has not been ...

Abstract	Covalent drug discovery has undergone a resurgence over the past two decades and reactive cysteine profiling has emerged in parallel as a platform for ligand discovery through on- and off-target profiling; however, the scope of this approach has not been fully explored at the whole-proteome level. We combined AlphaFold2-predicted side-chain accessibilities for >95% of the human proteome with a meta-analysis of eighteen public cysteine profiling datasets, totaling 44,187 unique cysteine residues, revealing accessibility biases in sampled cysteines primarily dictated by warhead chemistry. Analysis of >3.5 million cysteine-fragment interactions further showed that hit elaboration and optimization drives increased bias against buried cysteine residues. Based on these data, we suggest that current profiling approaches cover a small proportion of potential ligandable cysteine residues and propose future directions for increasing coverage, focusing on high-priority residues and depth. All analysis and produced resources are freely available and extendable to other reactive amino acids.
MeSH term(s)	Humans ; Cysteine/metabolism ; Proteome/metabolism ; Amino Acids ; Drug Discovery ; Ligands
Chemical Substances	Cysteine (K848JZ4886) ; Proteome ; Amino Acids ; Ligands
Language	English
Publishing date	2023-07-13
Publishing country	United States
Document type	Meta-Analysis ; Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2451-9448
ISSN (online)	2451-9448
DOI	10.1016/j.chembiol.2023.06.021
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Article ; Online: Protein lipidation in cancer: mechanisms, dysregulation and emerging drug targets.

Tate, Edward W / Soday, Lior / de la Lastra, Ana Losada / Wang, Mei / Lin, Hening

Nature reviews. Cancer

2024 Volume 24, Issue 4, Page(s) 240–260

Abstract: Protein lipidation describes a diverse class of post-translational modifications (PTMs) that is regulated by over 40 enzymes, targeting more than 1,000 substrates at over 3,000 sites. Lipidated proteins include more than 150 oncoproteins, including ... ...

Abstract	Protein lipidation describes a diverse class of post-translational modifications (PTMs) that is regulated by over 40 enzymes, targeting more than 1,000 substrates at over 3,000 sites. Lipidated proteins include more than 150 oncoproteins, including mediators of cancer initiation, progression and immunity, receptor kinases, transcription factors, G protein-coupled receptors and extracellular signalling proteins. Lipidation regulates the physical interactions of its protein substrates with cell membranes, regulating protein signalling and trafficking, and has a key role in metabolism and immunity. Targeting protein lipidation, therefore, offers a unique approach to modulate otherwise undruggable oncoproteins; however, the full spectrum of opportunities to target the dysregulation of these PTMs in cancer remains to be explored. This is attributable in part to the technological challenges of identifying the targets and the roles of protein lipidation. The early stage of drug discovery for many enzymes in the pathway contrasts with efforts for drugging similarly common PTMs such as phosphorylation and acetylation, which are routinely studied and targeted in relevant cancer contexts. Here, we review recent advances in identifying targetable protein lipidation pathways in cancer, the current state-of-the-art in drug discovery, and the status of ongoing clinical trials, which have the potential to deliver novel oncology therapeutics targeting protein lipidation.
MeSH term(s)	Humans ; Protein Processing, Post-Translational ; Neoplasms/drug therapy ; Phosphorylation ; Transcription Factors ; Oncogene Proteins
Chemical Substances	Transcription Factors ; Oncogene Proteins
Language	English
Publishing date	2024-02-29
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2062767-1
ISSN	1474-1768 ; 1474-175X
ISSN (online)	1474-1768
ISSN	1474-175X
DOI	10.1038/s41568-024-00666-x
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Zs.A 5563: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Dynamics and Molecular Interactions of GPI-Anchored CD59.

Voisin, Tomas B / Couves, Emma C / Tate, Edward W / Bubeck, Doryen

Toxins

2023 Volume 15, Issue 7

Abstract: CD59 is a GPI-anchored cell surface receptor that serves as a gatekeeper to controlling pore formation. It is the only membrane-bound inhibitor of the complement membrane attack complex (MAC), an immune pore that can damage human cells. While CD59 blocks ...

Abstract	CD59 is a GPI-anchored cell surface receptor that serves as a gatekeeper to controlling pore formation. It is the only membrane-bound inhibitor of the complement membrane attack complex (MAC), an immune pore that can damage human cells. While CD59 blocks MAC pores, the receptor is co-opted by bacterial pore-forming proteins to target human cells. Recent structures of CD59 in complexes with binding partners showed dramatic differences in the orientation of its ectodomain relative to the membrane. Here, we show how GPI-anchored CD59 can satisfy this diversity in binding modes. We present a PyLipID analysis of coarse-grain molecular dynamics simulations of a CD59-inhibited MAC to reveal residues of complement proteins (C6:Y285, C6:R407 C6:K412, C7:F224, C8β:F202, C8β:K326) that likely interact with lipids. Using modules of the MDAnalysis package to investigate atomistic simulations of GPI-anchored CD59, we discover properties of CD59 that encode the flexibility necessary to bind both complement proteins and bacterial virulence factors.
MeSH term(s)	Humans ; Complement Membrane Attack Complex/metabolism ; Complement System Proteins ; CD59 Antigens/chemistry ; CD59 Antigens/metabolism ; Bacteria/metabolism
Chemical Substances	Complement Membrane Attack Complex ; Complement System Proteins (9007-36-7) ; CD59 Antigens ; CD59 protein, human (101754-01-2)
Language	English
Publishing date	2023-06-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2518395-3
ISSN	2072-6651 ; 2072-6651
ISSN (online)	2072-6651
ISSN	2072-6651
DOI	10.3390/toxins15070430
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Article ; Online: XerC Is Required for the Repair of Antibiotic- and Immune-Mediated DNA Damage in Staphylococcus aureus.

Ledger, Elizabeth V K / Lau, Katie / Tate, Edward W / Edwards, Andrew M

Antimicrobial agents and chemotherapy

2023 Volume 67, Issue 3, Page(s) e0120622

Abstract: To survive in the host environment, pathogenic bacteria need to be able to repair DNA damage caused by both antibiotics and the immune system. The SOS response is a key bacterial pathway to repair DNA double-strand breaks and may therefore be a good ... ...

Abstract	To survive in the host environment, pathogenic bacteria need to be able to repair DNA damage caused by both antibiotics and the immune system. The SOS response is a key bacterial pathway to repair DNA double-strand breaks and may therefore be a good target for novel therapeutics to sensitize bacteria to antibiotics and the immune response. However, the genes required for the SOS response in Staphylococcus aureus have not been fully established. Therefore, we carried out a screen of mutants involved in various DNA repair pathways to understand which were required for induction of the SOS response. This led to the identification of 16 genes that may play a role in SOS response induction and, of these, 3 that affected the susceptibility of S. aureus to ciprofloxacin. Further characterization revealed that, in addition to ciprofloxacin, loss of the tyrosine recombinase XerC increased the susceptibility of S. aureus to various classes of antibiotics, as well as to host immune defenses. Therefore, the inhibition of XerC may be a viable therapeutic approach to sensitize S. aureus to both antibiotics and the immune response.
MeSH term(s)	Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/metabolism ; Staphylococcus aureus ; Ciprofloxacin/pharmacology ; Ciprofloxacin/metabolism ; DNA Damage/genetics ; DNA Repair/genetics
Chemical Substances	Anti-Bacterial Agents ; Ciprofloxacin (5E8K9I0O4U)
Language	English
Publishing date	2023-02-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	217602-6
ISSN	1098-6596 ; 0066-4804
ISSN (online)	1098-6596
ISSN	0066-4804
DOI	10.1128/aac.01206-22
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Zs.A 809: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Einzelsignatur: Show issues

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Article ; Online: Bacterial enzymes: powerful tools for protein labeling, cell signaling, and therapeutic discovery.

Liu, Lu / Gray, Janine L / Tate, Edward W / Yang, Aimin

Trends in biotechnology

2023 Volume 41, Issue 11, Page(s) 1385–1399

Abstract: Bacteria have evolved a diverse set of enzymes that enable them to subvert host defense mechanisms as well as to form part of the prokaryotic immune system. Due to their unique and varied biochemical activities, these bacterial enzymes have emerged as ... ...

Abstract	Bacteria have evolved a diverse set of enzymes that enable them to subvert host defense mechanisms as well as to form part of the prokaryotic immune system. Due to their unique and varied biochemical activities, these bacterial enzymes have emerged as key tools for understanding and investigating biological systems. In this review, we summarize and discuss some of the most prominent bacterial enzymes used for the site-specific modification of proteins, in vivo protein labeling, proximity labeling, interactome mapping, signaling pathway manipulation, and therapeutic discovery. Finally, we provide a perspective on the complementary advantages and limitations of using bacterial enzymes compared with chemical probes for exploring biological systems.
Language	English
Publishing date	2023-06-14
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	47474-5
ISSN	1879-3096 ; 0167-7799
ISSN (online)	1879-3096
ISSN	0167-7799
DOI	10.1016/j.tibtech.2023.05.004
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Article ; Online: Photoactive Bifunctional Degraders: Precision Tools To Regulate Protein Stability.

Kounde, Cyrille S / Tate, Edward W

Journal of medicinal chemistry

2020 Volume 63, Issue 24, Page(s) 15483–15493

Abstract: Targeted protein degradation with bifunctional degraders is positioned as a remarkable game-changing strategy to control cellular protein levels and promises a new therapeutic modality in drug discovery. Light activation of a degrader to achieve ... ...

Abstract	Targeted protein degradation with bifunctional degraders is positioned as a remarkable game-changing strategy to control cellular protein levels and promises a new therapeutic modality in drug discovery. Light activation of a degrader to achieve exquisite spatiotemporal control over protein stability in cells has attracted the interest of multiple research groups, with recent reports demonstrating optical control of proteolysis with chimeric molecules bearing photolabile or photoswitchable motifs. In this context of targeted proteolysis research spurring the emergence of innovative tools, we examine the design, synthesis, and properties of light-activated degraders. The significant impact of this approach in regulating disease-relevant protein levels in a light-dependent manner is highlighted with key examples, and future developments to fully harness the potential of light-induced protein degradation with photoactive bifunctional molecules are discussed.
MeSH term(s)	Animals ; Azo Compounds/chemistry ; Azo Compounds/pharmacology ; Cell Cycle Proteins/metabolism ; Cell Proliferation/drug effects ; Drug Design ; HeLa Cells ; Humans ; Light ; Proteasome Endopeptidase Complex/metabolism ; Protein Stability/radiation effects ; Proteins/metabolism ; Proteolysis/radiation effects ; Small Molecule Libraries/chemistry ; Small Molecule Libraries/pharmacology ; Transcription Factors/metabolism ; Ubiquitin-Protein Ligases/metabolism ; Zebrafish ; Zebrafish Proteins/chemistry ; Zebrafish Proteins/metabolism
Chemical Substances	Azo Compounds ; BRD4 protein, human ; Cell Cycle Proteins ; Proteins ; Small Molecule Libraries ; Transcription Factors ; Zebrafish Proteins ; Ubiquitin-Protein Ligases (EC 2.3.2.27) ; Proteasome Endopeptidase Complex (EC 3.4.25.1) ; azobenzene (F0U1H6UG5C)
Language	English
Publishing date	2020-11-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218133-2
ISSN	1520-4804 ; 0022-2623
ISSN (online)	1520-4804
ISSN	0022-2623
DOI	10.1021/acs.jmedchem.0c01542
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Zs.B 151: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Bacterial enzymes: powerful tools for protein labeling, cell signaling and therapeutic discovery

Liu, Lu / Gray, Janine L. / Tate, Edward W. / Yang, Aimin

Trends in Biotechnology.

2023

Abstract: Bacteria have evolved a diverse set of enzymes which enable them to subvert host defense mechanisms as well as to form part of the prokaryotic immune system. Due to their unique and varied biochemical activities, these bacterial enzymes have emerged as ... ...

Abstract	Bacteria have evolved a diverse set of enzymes which enable them to subvert host defense mechanisms as well as to form part of the prokaryotic immune system. Due to their unique and varied biochemical activities, these bacterial enzymes have emerged as key tools for understanding and investigating biological systems. In this review, we summarize and discuss some of the most prominent bacterial enzymes used for the site-specific modification of proteins, in vivo protein labeling, proximity labeling and interactome mapping, signaling pathway manipulation and in therapeutic discovery. Finally, we provide a perspective on the complementary advantages and limitations of using bacterial enzymes compared to chemical probes for exploring biological systems.
Keywords	biotechnology ; immune system ; therapeutics ; bacterial enzymes ; site-specific bioconjugation ; in vivo labeling ; proximity labeling ; signaling pathways ; therapeutic applications
Publishing place	Elsevier Ltd
Document type	Article ; Online
Note	Pre-press version
ZDB-ID	47474-5
ISSN	1879-3096 ; 0167-7799
ISSN (online)	1879-3096
ISSN	0167-7799
DOI	10.1016/j.tibtech.2023.05.004
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Evaluating Hedgehog Acyltransferase Activity and Inhibition Using the Acylation-coupled Lipophilic Induction of Polarization (Acyl-cLIP) Assay.

Andrei, Sebastian A / Tate, Edward W / Lanyon-Hogg, Thomas

Methods in molecular biology (Clifton, N.J.)

2021 Volume 2374, Page(s) 13–26

Abstract: Palmitoylation of the Hedgehog family of proteins is a critical step in the Hedgehog signaling pathway and is performed by the membrane-bound O-acyltransferase enzyme Hedgehog acyltransferase (HHAT). Measurement of HHAT activity has traditionally relied ... ...

Abstract	Palmitoylation of the Hedgehog family of proteins is a critical step in the Hedgehog signaling pathway and is performed by the membrane-bound O-acyltransferase enzyme Hedgehog acyltransferase (HHAT). Measurement of HHAT activity has traditionally relied on radiolabeled fatty acid substrates, which imposes considerable constraints on throughput, cost, and safety, consequently hindering the efficient identification and development of small-molecule HHAT inhibitors. The Acylation-coupled Lipophilic Induction of Polarisation (Acyl-cLIP) assay was recently developed in our lab as a novel platform to evaluate lipidation of peptides in real time and high throughput. In this chapter, we describe the isolation of active HHAT from HEK293a cells and application of the Acyl-cLIP assay to characterize HHAT inhibitors. Our methodology uses standard chemical biology lab equipment and yields high-quality kinetic data from minimal sample volumes. The assay uses standard 384-well plates and is easily adapted to medium- or high-throughput screening formats.
MeSH term(s)	Acylation ; Acyltransferases/metabolism ; Hedgehog Proteins/metabolism ; Lipoylation ; Surgical Instruments
Chemical Substances	Hedgehog Proteins ; Acyltransferases (EC 2.3.-)
Language	English
Publishing date	2021-09-25
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-0716-1701-4_2
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Article ; Online: Beyond targeted protein degradation: LD·ATTECs clear cellular lipid droplets.

De Vita, Elena / Lucy, Daniel / Tate, Edward W

Cell research

2021 Volume 31, Issue 9, Page(s) 945–946

MeSH term(s)	Lipid Droplets/metabolism ; Proteolysis
Language	English
Publishing date	2021-08-04
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	1319303-x
ISSN	1748-7838 ; 1001-0602
ISSN (online)	1748-7838
ISSN	1001-0602
DOI	10.1038/s41422-021-00546-1
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