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Yorodumi- PDB-9ay7: Crystal structure of CRAF/MEK1 complex with NST-628 and inactive RAF -
+Open data
-Basic information
Entry | Database: PDB / ID: 9ay7 | ||||||
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Title | Crystal structure of CRAF/MEK1 complex with NST-628 and inactive RAF | ||||||
Components |
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Keywords | TRANSFERASE / Inhibitor / complex / SIGNALING PROTEIN | ||||||
Function / homology | Function and homology information 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 / Rap1 signalling / Signaling by MAP2K mutants / regulation of cell motility / insulin secretion involved in cellular response to glucose stimulus / regulation of Golgi inheritance / spindle pole body / trachea formation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / regulation of stress-activated MAPK cascade / positive regulation of axonogenesis / GP1b-IX-V activation signalling / IFNG signaling activates MAPKs / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / regulation of cell differentiation / protein kinase activator activity / endodermal cell differentiation / MAPK3 (ERK1) activation / face development / pseudopodium / somatic stem cell population maintenance / MAP kinase kinase activity / Bergmann glial cell differentiation / thyroid gland development / neurotrophin TRK receptor signaling pathway / Uptake and function of anthrax toxins / extrinsic apoptotic signaling pathway via death domain receptors / MAP kinase kinase kinase activity / negative regulation of protein-containing complex assembly / Schwann cell development / type II interferon-mediated signaling pathway / activation of adenylate cyclase activity / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / keratinocyte differentiation / response to muscle stretch / ERK1 and ERK2 cascade / protein serine/threonine/tyrosine kinase activity / myelination / CD209 (DC-SIGN) signaling / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / insulin-like growth factor receptor signaling pathway / thymus development / Signal transduction by L1 / cell motility / RAF activation / wound healing / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / positive regulation of protein serine/threonine kinase activity / Stimuli-sensing channels / neuron differentiation / Negative regulation of MAPK pathway / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / chemotaxis / MAPK cascade / cellular senescence / Signaling by BRAF and RAF1 fusions / late endosome / insulin receptor signaling pathway / positive regulation of peptidyl-serine phosphorylation / heart development / scaffold protein binding / protein tyrosine kinase activity / regulation of apoptotic process / mitochondrial outer membrane / positive regulation of MAPK cascade / positive regulation of ERK1 and ERK2 cascade / early endosome / non-specific serine/threonine protein kinase / protein kinase activity / negative regulation of cell population proliferation / protein phosphorylation / protein serine kinase activity / focal adhesion / protein serine/threonine kinase activity / centrosome / positive regulation of gene expression / negative regulation of apoptotic process / apoptotic process / positive regulation of DNA-templated transcription Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.41 Å | ||||||
Authors | Quade, B. / Huang, X. | ||||||
Funding support | 1items
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Citation | Journal: Cancer Discov / Year: 2024 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. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 9ay7.cif.gz | 305.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb9ay7.ent.gz | Display | PDB format | |
PDBx/mmJSON format | 9ay7.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ay/9ay7 ftp://data.pdbj.org/pub/pdb/validation_reports/ay/9ay7 | HTTPS FTP |
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-Related structure data
Related structure data | 9axaC 9axcC 9axhC 9axmC 9axxC 9axyC 9ayaC C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
-Protein , 2 types, 2 molecules AB
#1: Protein | Mass: 31975.775 Da / Num. of mol.: 1 / Mutation: Y340D Y341D Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: RAF1, RAF / Production host: Homo sapiens (human) References: UniProt: P04049, non-specific serine/threonine protein kinase |
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#2: Protein | Mass: 43518.988 Da / Num. of mol.: 1 / Mutation: S218A S222A Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: MAP2K1, MEK1, PRKMK1 / Production host: Homo sapiens (human) References: UniProt: Q02750, mitogen-activated protein kinase kinase |
-Non-polymers , 7 types, 186 molecules
#3: Chemical | #4: Chemical | #5: Chemical | ChemComp-NI / | #6: Chemical | ChemComp-ACT / #7: Chemical | ChemComp-EDO / | #8: Chemical | ChemComp-A1AHE / | Mass: 488.464 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18F2N4O5S / Feature type: SUBJECT OF INVESTIGATION #9: Water | ChemComp-HOH / | |
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-Details
Has ligand of interest | Y |
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-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.49 Å3/Da / Density % sol: 50.69 % |
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Crystal grow | Temperature: 291 K / Method: vapor diffusion, sitting drop / pH: 8 / Details: 0.2M sodium acetate pH 8.0, 20% w/v PEG 3350 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
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Diffraction source | Source: SYNCHROTRON / Site: SPring-8 / Beamline: BL45XU / Wavelength: 1 Å |
Detector | Type: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: May 25, 2023 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1 Å / Relative weight: 1 |
Reflection | Resolution: 2.41→48.95 Å / Num. obs: 29864 / % possible obs: 100 % / Redundancy: 13.3 % / Biso Wilson estimate: 49.48 Å2 / Rmerge(I) obs: 0.112 / Net I/σ(I): 15.8 |
Reflection shell | Resolution: 2.41→2.5 Å / Rmerge(I) obs: 1.148 / Num. unique obs: 2786 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.41→48.95 Å / SU ML: 0.2948 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 24.6551 Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
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Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 58.5 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.41→48.95 Å
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Refine LS restraints |
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LS refinement shell |
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Refinement TLS params. | Method: refined / Origin x: -17.5524925115 Å / Origin y: 1.37446586767 Å / Origin z: -22.9292303617 Å
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Refinement TLS group | Selection details: all |