scholarly journals Selective inhibition of cullin 3 neddylation through covalent targeting DCN1 protects mice from acetaminophen-induced liver toxicity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Haibin Zhou ◽  
Jianfeng Lu ◽  
Krishnapriya Chinnaswamy ◽  
Jeanne A. Stuckey ◽  
Liu Liu ◽  
...  
Keyword(s):  
Liver Toxicity ◽  
Therapeutic Potential ◽  
Protein A ◽  
Covalent Bond ◽  
Selective Inhibition ◽  
Spectrometric Analysis ◽  
E3 Ligases ◽  
Cullin 3 ◽  
Covalent Bond Formation ◽  
Ring E3 Ligases

AbstractCullin-RING E3 ligases (CRLs) regulate the turnover of approximately 20% of mammalian cellular proteins. Neddylation of individual cullin proteins is essential for the activation of each CRL. We report herein the discovery of DI-1548 and DI-1859 as two potent, selective and covalent DCN1 inhibitors. These inhibitors selectively inhibit neddylation of cullin 3 in cells at low nanomolar concentrations and are 2–3 orders of magnitude more potent than our previously reported reversible DCN1 inhibitor. Mass spectrometric analysis and co-crystal structures reveal that these compounds employ a unique mechanism of covalent bond formation with DCN1. DI-1859 induces a robust increase of NRF2 protein, a CRL3 substrate, in mouse liver and effectively protects mice from acetaminophen-induced liver damage. Taken together, this study demonstrates the therapeutic potential of selective inhibition of cullin neddylation.

scholarly journals A Nut for Every Bolt: Subunit-Selective Inhibitors of the Immunoproteasome and Their Therapeutic Potential

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1929
Author(s):  
Eva M. Huber ◽  
Michael Groll
Keyword(s):  
Cell Cycle Progression ◽  
Therapeutic Potential ◽  
Cell Signalling ◽  
Selective Inhibition ◽  
Ubiquitin Proteasome System ◽  
Cellular Processes ◽  
Chemical Structures ◽  
Phase Ii Clinical Trials ◽  
Ubiquitin Proteasome ◽  
Recent Trends

At the heart of the ubiquitin–proteasome system, the 20S proteasome core particle (CP) breaks down the majority of intracellular proteins tagged for destruction. Thereby, the CP controls many cellular processes including cell cycle progression and cell signalling. Inhibitors of the CP can suppress these essential biological pathways, resulting in cytotoxicity, an effect that is beneficial for the treatment of certain blood cancer patients. During the last decade, several preclinical studies demonstrated that selective inhibition of the immunoproteasome (iCP), one of several CP variants in mammals, suppresses autoimmune diseases without inducing toxic side effects. These promising findings led to the identification of natural and synthetic iCP inhibitors with distinct chemical structures, varying potency and subunit selectivity. This review presents the most prominent iCP inhibitors with respect to possible scientific and medicinal applications, and discloses recent trends towards pan-immunoproteasome reactive inhibitors that cumulated in phase II clinical trials of the lead compound KZR-616 for chronic inflammations.

scholarly journals Physical and chemical imaging of adhesive interfaces with soft X-rays

2021 ◽  
Vol 2 (1) ◽  
Author(s):  
Hiroyuki Yamane ◽  
Masaki Oura ◽  
Osamu Takahashi ◽  
Tomoko Ishihara ◽  
Noriko Yamazaki ◽  
...  
Keyword(s):  
Molecular Level ◽  
Covalent Bond ◽  
Chemical Imaging ◽  
Diglycidyl Ether ◽  
X Rays ◽  
X Ray ◽  
Covalent Bond Formation ◽  
Chemical States ◽  
The Individual ◽  
Physical And Chemical

AbstractAdhesion is an interfacial phenomenon that is critical for assembling carbon structural composites for next-generation aircraft and automobiles. However, there is limited understanding of adhesion on the molecular level because of the difficulty in revealing the individual bonding factors. Here, using soft X-ray spectromicroscopy we show the physical and chemical states of an adhesive interface composed of a thermosetting polymer of 4,4’-diaminodiphenylsulfone-cured bisphenol A diglycidyl ether adhered to a thermoplastic polymer of plasma-treated polyetheretherketone. We observe multiscale phenomena in the adhesion mechanisms, including sub-mm complex interface structure, sub-μm distribution of the functional groups, and molecular-level covalent-bond formation. These results provide a benchmark for further research to examine how physical and chemical states correlate with adhesion, and demonstrate that soft X-ray imaging is a promising approach for visualizing the physical and chemical states at adhesive interfaces from the sub-mm level to the molecular level.

scholarly journals Chemical Investigations Into the Biosynthesis of the Gymnastatin and Dankastatin Alkaloids

2021 ◽  
Author(s):  
Bingqi Tong ◽  
Bridget Belcher ◽  
Daniel Nomura ◽  
Thomas Maimone
Keyword(s):  
Natural Products ◽  
Protein Function ◽  
Bond Formation ◽  
Covalent Bond ◽  
Fungal Strain ◽  
Fertile Ground ◽  
Covalent Bond Formation

Electrophilic natural products have provided fertile ground for understanding how nature inhibits protein function using covalent bond formation. The fungal strain Gymnascella dankaliensis has provided an especially interesting collection of...

Material Adhesion through Direct Covalent Bond Formation Assisted by Noncovalent Interactions

2021 ◽  
Author(s):  
Motofumi Osaki ◽  
Tomoko Sekine ◽  
Hiroyasu Yamaguchi ◽  
Yoshinori Takashima ◽  
Akira Harada
Keyword(s):  
Noncovalent Interactions ◽  
Bond Formation ◽  
Covalent Bond ◽  
Covalent Bond Formation

scholarly journals Arabidopsis DREB2A-Interacting Proteins Function as RING E3 Ligases and Negatively Regulate Plant Drought Stress–Responsive Gene Expression

2008 ◽  
Vol 20 (6) ◽  
pp. 1693-1707 ◽  
Author(s):  
Feng Qin ◽  
Yoh Sakuma ◽  
Lam-Son Phan Tran ◽  
Kyonoshin Maruyama ◽  
Satoshi Kidokoro ◽  
...  
Keyword(s):  
Gene Expression ◽  
Drought Stress ◽  
Interacting Proteins ◽  
E3 Ligases ◽  
Responsive Gene ◽  
Ring E3 Ligases ◽  
Ring E3

scholarly journals Molecular recognition of organic ammonium ions in solution using synthetic receptors

2010 ◽  
Vol 6 ◽  
Author(s):  
Andreas Späth ◽  
Burkhard König
Keyword(s):  
Molecular Recognition ◽  
Hydrophobic Interactions ◽  
Covalent Bond ◽  
Ammonium Ion ◽  
Synthetic Receptors ◽  
Ammonium Ions ◽  
Wide Range ◽  
Covalent Bond Formation ◽  
Reversible Covalent ◽  
Ion Receptors

Ammonium ions are ubiquitous in chemistry and molecular biology. Considerable efforts have been undertaken to develop synthetic receptors for their selective molecular recognition. The type of host compounds for organic ammonium ion binding span a wide range from crown ethers to calixarenes to metal complexes. Typical intermolecular interactions are hydrogen bonds, electrostatic and cation–π interactions, hydrophobic interactions or reversible covalent bond formation. In this review we discuss the different classes of synthetic receptors for organic ammonium ion recognition and illustrate the scope and limitations of each class with selected examples from the recent literature. The molecular recognition of ammonium ions in amino acids is included and the enantioselective binding of chiral ammonium ions by synthetic receptors is also covered. In our conclusion we compare the strengths and weaknesses of the different types of ammonium ion receptors which may help to select the best approach for specific applications.

scholarly journals Saccharomyces cerevisiae ubiquitin-like protein Rub1 conjugates to cullin proteins Rtt101 and Cul3 in vivo

2004 ◽  
Vol 377 (2) ◽  
pp. 459-467 ◽  
Author(s):  
Jose M. LAPLAZA ◽  
Magnolia BOSTICK ◽  
Derek T. SCHOLES ◽  
M. Joan CURCIO ◽  
Judy CALLIS
Keyword(s):  
Saccharomyces Cerevisiae ◽  
Protein A ◽  
Fold Increase ◽  
Lysine Residue ◽  
Reading Frame ◽  
E3 Ligases ◽  
C Terminus ◽  
Dependent Modification ◽  
F Box Protein

In Saccharomyces cerevisiae, the ubiquitin-like protein Rub1p (related to ubiquitin 1 protein) covalently attaches to the cullin protein Cdc53p (cell division cycle 53 protein), a subunit of a class of ubiquitin E3 ligases named SCF (Skp1–Cdc53–F-box protein) complex. We identified Rtt101p (regulator of Ty transposition 101 protein, where Ty stands for transposon of yeast), initially found during a screen for proteins to confer retrotransposition suppression, and Cul3p (cullin 3 protein), a protein encoded by the previously uncharacterized open reading frame YGR003w, as two new in vivo targets for Rub1p conjugation. These proteins show significant identity with Cdc53p and, therefore, are cullin proteins. Modification of Cul3p is eliminated by deletion of the Rub1p pathway through disruption of either RUB1 or its activating enzyme ENR2/ULA1. The same disruptions in the Rub pathway decreased the percentage of total Rtt101p that is modified from approx. 60 to 30%. This suggests that Rtt101p has an additional RUB1- and ENR2-independent modification. All modified forms of Rtt101p and Cul3p were lost when a single lysine residue in a conserved region near the C-terminus was replaced by an arginine residue. These results suggest that this lysine residue is the site of Rub1p-dependent and -independent modifications in Rtt101p and of Rub1p-dependent modification in Cul3p. An rtt101Δ strain was hypersensitive to thiabendazole, isopropyl (N-3-chlorophenyl) carbamate and methyl methanesulphonate, but rub1Δ strains were not. Whereas rtt101Δ strains exhibited a 14-fold increase in Ty1 transposition, isogenic rub1Δ strains did not show statistically significant increases. Rtt101K791Rp, which cannot be modified, complemented for Rtt101p function in a transposition assay. Altogether, these results suggest that neither the RUB1-dependent nor the RUB1-independent form of Rtt101p is required for Rtt101p function. The identification of additional Rub1p targets in S. cerevisiae suggests an expanded role for Rub in this organism.

scholarly journals Identification of a PGXPP degron motif in dishevelled and structural basis for its binding to the E3 ligase KLHL12

Open Biology ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 200041 ◽  
Author(s):  
Zhuoyao Chen ◽  
Gregory A. Wasney ◽  
Sarah Picaud ◽  
Panagis Filippakopoulos ◽  
Masoud Vedadi ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Molecular Mechanisms ◽  
Hydrophobic Interactions ◽  
E3 Ubiquitin Ligase ◽  
Structural Basis ◽  
E3 Ligases ◽  
Kelch Domain ◽  
Ring E3 Ligases ◽  
Ring E3 ◽  
New Protein

Wnt signalling is dependent on dishevelled proteins (DVL1-3), which assemble an intracellular Wnt signalosome at the plasma membrane. The levels of DVL1-3 are regulated by multiple Cullin-RING E3 ligases that mediate their ubiquitination and degradation. The BTB-Kelch protein KLHL12 was the first E3 ubiquitin ligase to be identified for DVL1-3, but the molecular mechanisms determining its substrate interactions have remained unknown. Here, we mapped the interaction of DVL1-3 to a ‘PGXPP' motif that is conserved in other known partners and substrates of KLHL12, including PLEKHA4, PEF1, SEC31 and DRD4. To determine the binding mechanism, we solved a 2.4 Å crystal structure of the Kelch domain of KLHL12 in complex with a DVL1 peptide that bound with low micromolar affinity. The DVL1 substrate adopted a U-shaped turn conformation that enabled hydrophobic interactions with all six blades of the Kelch domain β-propeller. In cells, the mutation or deletion of this motif reduced the binding and ubiquitination of DVL1 and increased its stability confirming this sequence as a degron motif for KLHL12 recruitment. These results define the molecular mechanisms determining DVL regulation by KLHL12 and establish the KLHL12 Kelch domain as a new protein interaction module for a novel proline-rich motif.

scholarly journals Mechanism of Covalent Binding of Ibrutinib to Bruton’s Tyrosine Kinase revealed by QM/MM Calculations

2020 ◽  
Author(s):  
Angus Voice ◽  
Gary Tresadern ◽  
Rebecca Twidale ◽  
Herman Van Vlijmen ◽  
Adrian Mulholland
Keyword(s):  
Tyrosine Kinase ◽  
Covalent Binding ◽  
Bond Formation ◽  
Covalent Bond ◽  
Covalent Modification ◽  
Mechanistic Study ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Covalent Inhibitors ◽  
Covalent Bond Formation

<p>Ibrutinib is the first covalent inhibitor of Bruton’s tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition is crucial for the design of safer and more selective covalent inhibitors that target BTK. There are questions surrounding the precise mechanism of covalent bond formation in BTK as there is no appropriate active site residue that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. To address this, we have investigated several mechanistic pathways of covalent modification of C481 in BTK by ibrutinib using QM/MM reaction simulations. The lowest energy pathway we identified involves a direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto-enol tautomerisation step (DG<sup>‡</sup>=10.5 kcal mol<sup>-1</sup>) to reach the inactivated BTK/ibrutinib complex. Our results represent the first mechanistic study of BTK inactivation by ibrutinib to consider multiple mechanistic pathways. These findings should aid in the design of covalent drugs that target BTK and related proteins. </p>

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