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- PDB-9axa: CryoEM structure of activated CRAF/MEK/14-3-3 complex with NST-628 -
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Open data
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Basic information
Entry | Database: PDB / ID: 9axa | ||||||
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Title | CryoEM structure of activated CRAF/MEK/14-3-3 complex with NST-628 | ||||||
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![]() | TRANSFERASE / Inhibitor / complex / SIGNALING PROTEIN | ||||||
Function / homology | ![]() death-inducing signaling complex assembly / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / intermediate filament cytoskeleton organization / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / labyrinthine layer development / MAP-kinase scaffold activity / type B pancreatic cell proliferation ...death-inducing signaling complex assembly / epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / intermediate filament cytoskeleton organization / placenta blood vessel development / regulation of axon regeneration / mitogen-activated protein kinase kinase / labyrinthine layer development / MAP-kinase scaffold activity / type B pancreatic cell proliferation / cerebellar cortex formation / regulation of Rho protein signal transduction / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / Signaling by MAP2K mutants / Rap1 signalling / regulation of cell motility / insulin secretion involved in cellular response to glucose stimulus / regulation of Golgi inheritance / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / positive regulation of axonogenesis / regulation of stress-activated MAPK cascade / IFNG signaling activates MAPKs / Frs2-mediated activation / GP1b-IX-V activation signalling / ERBB2-ERBB3 signaling pathway / regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / protein kinase activator activity / keratinization / endodermal cell differentiation / regulation of cell differentiation / face development / MAPK3 (ERK1) activation / pseudopodium / somatic stem cell population maintenance / Bergmann glial cell differentiation / MAP kinase kinase activity / thyroid gland development / neurotrophin TRK receptor signaling pathway / glutathione transferase / Uptake and function of anthrax toxins / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / glutathione transferase activity / extrinsic apoptotic signaling pathway via death domain receptors / phosphoserine residue binding / MAP kinase kinase kinase activity / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / establishment of skin barrier / negative regulation of protein-containing complex assembly / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Schwann cell development / type II interferon-mediated signaling pathway / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / negative regulation of stem cell proliferation / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / RHO GTPases activate PKNs / keratinocyte differentiation / protein kinase A signaling / protein sequestering activity / activation of adenylate cyclase activity / response to muscle stretch / ERK1 and ERK2 cascade / negative regulation of innate immune response / protein serine/threonine/tyrosine kinase activity / myelination / protein export from nucleus / CD209 (DC-SIGN) signaling / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / glutathione metabolic process / insulin-like growth factor receptor signaling pathway / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / positive regulation of protein export from nucleus / release of cytochrome c from mitochondria / thymus development / stem cell proliferation / Signal transduction by L1 / Translocation of SLC2A4 (GLUT4) to the plasma membrane / cell motility / TP53 Regulates Metabolic Genes / RAF activation / negative regulation of protein kinase activity / Signaling by high-kinase activity BRAF mutants / wound healing / MAP2K and MAPK activation / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / positive regulation of protein serine/threonine kinase activity / neuron differentiation / Stimuli-sensing channels / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.36 Å | ||||||
![]() | Quade, B. / Cohen, S.E. / Huang, X. | ||||||
Funding support | 1items
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![]() | ![]() Title: The Pan-RAF-MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS-MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers. Authors: Meagan B Ryan / Bradley Quade / Natasha Schenk / Zhong Fang / Marshall Zingg / Steven E Cohen / Brooke M Swalm / Chun Li / Ayşegül Özen / Chaoyang Ye / Maria Stella Ritorto / Xin Huang / ...Authors: Meagan B Ryan / Bradley Quade / Natasha Schenk / Zhong Fang / Marshall Zingg / Steven E Cohen / Brooke M Swalm / Chun Li / Ayşegül Özen / Chaoyang Ye / Maria Stella Ritorto / Xin Huang / Arvin C Dar / Yongxin Han / Klaus P Hoeflich / Michael Hale / Margit Hagel / ![]() Abstract: Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the ...Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analyses of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies, NST-628 is positioned to make an impact clinically in areas of unmet patient need. Significance: This study introduces NST-628, a molecular glue having differentiated mechanism and drug-like properties. NST-628 treatment leads to broad efficacy with high tolerability and central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 has the potential to provide transformative clinical benefits as both monotherapy and vertical combination anchor. | ||||||
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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PDBx/mmCIF format | ![]() | 304.5 KB | Display | ![]() |
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PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 1.1 MB | Display | ![]() |
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Full document | ![]() | 1.1 MB | Display | |
Data in XML | ![]() | 51.2 KB | Display | |
Data in CIF | ![]() | 75.2 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 43931MC ![]() 9axcC ![]() 9axhC ![]() 9axmC ![]() 9axxC ![]() 9axyC ![]() 9ay7C ![]() 9ayaC M: map data used to model this data C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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Components
#1: Protein | Mass: 64798.465 Da / Num. of mol.: 2 / Mutation: Y340D Y341D Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: P08515, UniProt: P04049, glutathione transferase, non-specific serine/threonine protein kinase #2: Protein | Mass: 43518.988 Da / Num. of mol.: 2 / Mutation: S218A S222A Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() References: UniProt: Q02750, mitogen-activated protein kinase kinase #3: Protein | Mass: 27807.064 Da / Num. of mol.: 2 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() #4: Chemical | Mass: 488.464 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H18F2N4O5S / Feature type: SUBJECT OF INVESTIGATION Has ligand of interest | Y | |
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-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: CRAF/MEK/14-3-3 complex with NST-628 / Type: COMPLEX / Entity ID: #1-#3 / Source: RECOMBINANT |
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Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
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Electron microscopy imaging
Microscopy | Model: TFS GLACIOS |
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Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 4.36 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 83248 / Symmetry type: POINT |
Refinement | Cross valid method: NONE |