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| Open AccessStructural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine
The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. Herein, the authors report the NMR solution structures of a bulge-containing KRAS-G4 that bound to two small molecules. The study provides molecular details of ligand interactions with KRAS-G4 and contributes insight into the design of specific KRAS-G4-interactive drugs.
- Kai-Bo Wang
- , Yushuang Liu
- & Ling-Yi Kong
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Article
| Open AccessPhase transition and remodeling complex assembly are important for SS18-SSX oncogenic activity in synovial sarcomas
Oncoprotein SS18-SSX is a hallmark of synovial sarcoma. Here the authors report phase separation of SS18-SSX and the binding of SS18-SSX to chromatin remodeling complex are important for the transformation activity of the oncoprotein SS18-SSX.
- Yanli Cheng
- , Zhongtian Shen
- & Jiafu Long
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| Open AccessLeveraging the multivalent p53 peptide-MdmX interaction to guide the improvement of small molecule inhibitors
Peptide fragments derived from the interfaces of protein-protein interactions (PPIs) provide useful templates for designing small molecule PPI inhibitors. Here, the authors utilize the multivalency of an MdmX-binding p53 peptide to develop a weak inhibitor of MdmX into potent Mdm2/MdmX inhibitors.
- Xiyao Cheng
- , Rong Chen
- & Zhengding Su
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Article
| Open AccessThe conformational stability of pro-apoptotic BAX is dictated by discrete residues of the protein core
The pro-apoptotic BAX protein is a monomer under homeostatic conditions and, in response to stress, transforms into oligomers that induce apoptosis. Here, the authors characterize structural features of BAX that individually stabilize the monomer while collectively contributing to oligomerization.
- Noah B. Bloch
- , Thomas E. Wales
- & Loren D. Walensky
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Article
| Open AccessEngineering an anti-HER2 biparatopic antibody with a multimodal mechanism of action
HER2 acts an oncogenic driver in numerous cancers. Here, the authors design an anti-HER2 biparatopic and tetravalent IgG fusion with inhibitory effects in a xenograft model.
- Florian Kast
- , Martin Schwill
- & Andreas Plückthun
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Article
| Open AccessStructure–function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting
An EGFR mutant with kinase domain duplication (EGFR-KDD) was previously identified in an index patient, but the functional and therapeutic implications remain unclear. Here, the authors show that KDD occurs in other ErbB receptors in multiple cancers, and characterize the mechanism and inhibition of EGFR-KDD.
- Zhenfang Du
- , Benjamin P. Brown
- & Christine M. Lovly
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Article
| Open AccessKRAS interaction with RAF1 RAS-binding domain and cysteine-rich domain provides insights into RAS-mediated RAF activation
The molecular details of the RAS-RAF interaction are still not fully understood. Here, the authors present crystal structures of wild-type and mutant KRAS in complex with the RAS-binding and membrane-interacting cysteine-rich domains of RAF1, and propose a model of the membrane-bound RAS-RAF complex.
- Timothy H. Tran
- , Albert H. Chan
- & Dhirendra K. Simanshu
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Article
| Open AccessMutant-selective degradation by BRAF-targeting PROTACs
Hundreds of BRAF mutations have been identified in patients with cancer but currently approved drugs only target BRAF V600 mutants. Here, the authors develop a vemurafenib-based PROTAC that induces degradation of all classes of BRAF mutants without affecting wild-type RAF proteins.
- Shanique Alabi
- , Saul Jaime-Figueroa
- & Craig M. Crews
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Article
| Open AccessSelective inhibition of STAT3 signaling using monobodies targeting the coiled-coil and N-terminal domains
STAT3 is an attractive therapeutic target but its homology with other STAT proteins complicates the development of selective inhibitors. Here, the authors develop monobodies with high affinity and selectivity for STAT3 and show that they can interfere with cellular STAT3 activity.
- Grégory La Sala
- , Camille Michiels
- & Oliver Hantschel
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Article
| Open AccessA potent KRAS macromolecule degrader specifically targeting tumours with mutant KRAS
Targeted protein degradation is an attractive therapeutic strategy to deplete oncogenic proteins in tumours. Here the authors demonstrate the specific targeting of endogenous KRAS protein for degradation from cancer cells, and regression of tumours expressing mutant KRAS in a mouse model.
- Nicolas Bery
- , Ami Miller
- & Terry Rabbitts
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Article
| Open AccessA central role of IKK2 and TPL2 in JNK activation and viral B-cell transformation
IKK2 is the main mediator of the NF-kappaB pathway. Here, the authors demonstrate that LMP1 sustains the survival of Epstein-Barr virus-transformed human B cells and post-transplant lymphoma through IKK2 that induces JNK signaling through TPL2.
- Stefanie Voigt
- , Kai R. Sterz
- & Arnd Kieser
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Article
| Open AccessStructures of BCL-2 in complex with venetoclax reveal the molecular basis of resistance mutations
The BCL-2 mutation G101V reduces venetoclax affinity and confers drug resistance in patients with chronic lymphocytic leukaemia. Here, the authors present crystal structures and biochemical analyses of venetoclax bound to BCL-2 and the G101V mutant, revealing the structural basis for venetoclax resistance.
- Richard W. Birkinshaw
- , Jia-nan Gong
- & Peter E. Czabotar
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Article
| Open AccessNucleoporin Nup155 is part of the p53 network in liver cancer
The nuclear pore complex (NPC) is known to regulate p53 signaling and this has mainly been linked to peripheral NPC subunits. Here the authors show that Nup155 from the NPC inner ring regulates the p53 pathway by controlling p21 translation while also being a target of p53-mediated repression.
- Kerstin Holzer
- , Alessandro Ori
- & Stephan Singer
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Article
| Open AccessWDR76 is a RAS binding protein that functions as a tumor suppressor via RAS degradation
Overexpression of RAS proteins is frequently observed in patients with hepatocellular carcinoma. Here, the authors identify an HRAS binding protein, the E3 ubiquitin ligase WDR76, which promotes HRAS degradation, thus functioning as a tumour suppressor in liver cancer
- Woo-Jeong Jeong
- , Jong-Chan Park
- & Kang-Yell Choi
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| Open AccessInterrogating the protein interactomes of RAS isoforms identifies PIP5K1A as a KRAS-specific vulnerability
RAS isoforms are frequently mutated in cancer but their inhibition remains challenging. By comparing the protein interactomes of the highly similar isoforms HRAS, NRAS and KRAS, the authors here identify PIP5K1A as a KRAS-specific interactor and a target to inhibit KRAS-driven cell growth.
- Hema Adhikari
- & Christopher M. Counter
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Article
| Open AccessHIF-2α-pVHL complex reveals broad genotype-phenotype correlations in HIF-2α-driven disease
Hypoxia inducible factor (HIF)-2α transcription factor is mutated in polycythemia and various neuroendocrine tumors. Here the authors present the crystal structure of a HIF-2α peptide bound to the pVHL-elongin B-elongin C (VBC) heterotrimeric complex and propose a classification scheme for HIF-2α mutations that helps to predict disease phenotype outcome.
- Daniel Tarade
- , Claire M. Robinson
- & Michael Ohh
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| Open AccessSmall molecule inhibitors of RAS-effector protein interactions derived using an intracellular antibody fragment
Intracellular antibodies can inhibit disease-relevant protein interactions, but inefficient cellular uptake limits their utility. Using a RAS-targeting intracellular antibody as a screening tool, the authors here identify small molecules that inhibit RAS-effector interactions and readily penetrate cells.
- Camilo E. Quevedo
- , Abimael Cruz-Migoni
- & Terence H. Rabbitts
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Conversion of the LIMA1 tumour suppressor into an oncogenic LMO-like protein by API2–MALT1 in MALT lymphoma
Protein fusions between the paracaspase MALT1 and API2 (inhibitor of apoptosis 2) are found in B-cell lymphoma. Here the authors identify the tumour suppressor LIMA1 as a new target of API2–MALT1 chimeric protein and show that API2–MALT1-mediated proteolysis generates a LIM domain-only (LMO)-containing fragment with oncogenic properties in vitro and in vivo.
- Zilin Nie
- , Ming-Qing Du
- & Kojo S. J. Elenitoba-Johnson
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TCTP directly regulates ATM activity to control genome stability and organ development in Drosophila melanogaster
Human TCTP, a highly conserved protein linked to tumorigenesis, has been implicated in the cellular DNA damage response in an ATM kinase-dependent manner. Here, Hong et al. demonstrate in vivo that DrosophiladTCTP controls genome stability by enhancing dATM activity towards its substrate H2Av.
- Sung-Tae Hong
- & Kwang-Wook Choi
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Cyclin D1 induction of Dicer governs microRNA processing and expression in breast cancer
Whether microRNA processing mediated by Dicer is regulated in a cell-cycle-dependent manner is unknown. Here, Chen et al.show that Cyclin D1, which is important in the control of the cell cycle, regulates the expression of Dicer, and that Cyclin D1 and Dicer expression levels correlate in breast cancer.
- Zuoren Yu
- , Liping Wang
- & Richard G. Pestell
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The metastasis-promoting S100A4 protein confers neuroprotection in brain injury
Multifunctional S100 proteins are upregulated in brain injury, but their role in neurodegeneration is not clear. Dmytriyeva and colleagues study in vivomodels of brain trauma and find that the S100A4 protein and its peptide mimetics protect neurons via the interleukin-10 receptor and the Janus kinase (JAK)/STAT pathway.
- Oksana Dmytriyeva
- , Stanislava Pankratova
- & Darya Kiryushko
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Article
| Open AccessAn intrinsically labile α-helix abutting the BCL9-binding site of β-catenin is required for its inhibition by carnosic acid
β-Catenin can be oncogenic but finding inhibitors has been a challenge. Here, five compounds are identified, which attenuate transcriptional β-catenin outputs in colorectal cancer cells, and the response to one of them is shown to require an intrinsically labile α-helix next to the BCL9-binding site in β-catenin.
- Marc de la Roche
- , Trevor J. Rutherford
- & Mariann Bienz