[English] 日本語
![](img/lk-miru.gif)
- PDB-9axy: Crystal structure of BRAF/MEK complex with NST-628 and inactive RAF -
+
Open data
-
Basic information
Entry | Database: PDB / ID: 9axy | ||||||
---|---|---|---|---|---|---|---|
Title | Crystal structure of BRAF/MEK complex with NST-628 and inactive RAF | ||||||
![]() |
| ||||||
![]() | TRANSFERASE / Inhibitor / complex / SIGNALING PROTEIN | ||||||
Function / homology | ![]() epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / trehalose metabolism in response to stress / regulation of axon regeneration / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / mitogen-activated protein kinase kinase / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development ...epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / CD4-positive, alpha-beta T cell differentiation / placenta blood vessel development / trehalose metabolism in response to stress / regulation of axon regeneration / CD4-positive or CD8-positive, alpha-beta T cell lineage commitment / mitogen-activated protein kinase kinase / negative regulation of synaptic vesicle exocytosis / labyrinthine layer development / MAP-kinase scaffold activity / type B pancreatic cell proliferation / Signalling to p38 via RIT and RIN / cerebellar cortex formation / head morphogenesis / myeloid progenitor cell differentiation / ARMS-mediated activation / SHOC2 M1731 mutant abolishes MRAS complex function / Gain-of-function MRAS complexes activate RAF signaling / endothelial cell apoptotic process / Signaling by MAP2K mutants / negative regulation of fibroblast migration / positive regulation of glucose transmembrane transport / establishment of protein localization to membrane / regulation of Golgi inheritance / mitogen-activated protein kinase kinase binding / trachea formation / regulation of T cell differentiation / Negative feedback regulation of MAPK pathway / regulation of early endosome to late endosome transport / positive regulation of axonogenesis / regulation of stress-activated MAPK cascade / Frs2-mediated activation / ERBB2-ERBB3 signaling pathway / stress fiber assembly / positive regulation of axon regeneration / protein kinase activator activity / endodermal cell differentiation / face development / MAPK3 (ERK1) activation / synaptic vesicle exocytosis / somatic stem cell population maintenance / Bergmann glial cell differentiation / MAP kinase kinase activity / thyroid gland development / Uptake and function of anthrax toxins / MAP kinase kinase kinase activity / Schwann cell development / negative regulation of endothelial cell apoptotic process / positive regulation of substrate adhesion-dependent cell spreading / keratinocyte differentiation / positive regulation of stress fiber assembly / response to cAMP / cellular response to calcium ion / ERK1 and ERK2 cascade / protein serine/threonine/tyrosine kinase activity / myelination / protein serine/threonine kinase activator activity / MAP3K8 (TPL2)-dependent MAPK1/3 activation / substrate adhesion-dependent cell spreading / insulin-like growth factor receptor signaling pathway / cellular response to nerve growth factor stimulus / thymus development / Signal transduction by L1 / cell motility / long-term synaptic potentiation / animal organ morphogenesis / RAF activation / Spry regulation of FGF signaling / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / visual learning / positive regulation of protein serine/threonine kinase activity / neuron differentiation / epidermal growth factor receptor signaling pathway / response to peptide hormone / 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 / cellular response to xenobiotic stimulus / late endosome / presynapse / positive regulation of peptidyl-serine phosphorylation / heart development / T cell receptor signaling pathway / regulation of cell population proliferation / cell body / T cell differentiation in thymus / scaffold protein binding / protein tyrosine kinase activity / negative regulation of neuron apoptotic process / Ras protein signal transduction / positive regulation of ERK1 and ERK2 cascade / early endosome Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Quade, B. / Huang, X. | ||||||
Funding support | 1items
| ||||||
![]() | ![]() 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 |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 303.7 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 1.2 MB | Display | ![]() |
---|---|---|---|---|
Full document | ![]() | 1.2 MB | Display | |
Data in XML | ![]() | 22.7 KB | Display | |
Data in CIF | ![]() | 30.1 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 9axaC ![]() 9axcC ![]() 9axhC ![]() 9axmC ![]() 9axxC ![]() 9ay7C ![]() 9ayaC C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
| ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 |
| ||||||||||||
Unit cell |
|
-
Components
#1: Protein | Mass: 31826.807 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: P15056, non-specific serine/threonine protein kinase | ||||||
---|---|---|---|---|---|---|---|
#2: Protein | Mass: 43518.988 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: Q02750, mitogen-activated protein kinase kinase | ||||||
#3: Chemical | #4: Chemical | #5: Chemical | ChemComp-A1AHE / | Mass: 488.464 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H18F2N4O5S / Feature type: SUBJECT OF INVESTIGATION Has ligand of interest | Y | |
-Experimental details
-Experiment
Experiment | Method: ![]() |
---|
-
Sample preparation
Crystal | Density Matthews: 3.4 Å3/Da / Density % sol: 63.82 % |
---|---|
Crystal grow | Temperature: 291 K / Method: vapor diffusion, hanging drop / pH: 8 Details: 0.2 M Lithium chloride, 0.1 M TRIS pH 8, 20% w/v PEG 8000 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
---|---|
Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: DECTRIS EIGER2 S 9M / Detector: PIXEL / Date: Dec 16, 2022 |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.97918 Å / Relative weight: 1 |
Reflection | Resolution: 3.6→53.34 Å / Num. obs: 12215 / % possible obs: 99.5 % / Redundancy: 12.6 % / Biso Wilson estimate: 85.16 Å2 / Rmerge(I) obs: 0.257 / Net I/σ(I): 8.5 |
Reflection shell | Resolution: 3.6→3.94 Å / Rmerge(I) obs: 0.918 / Num. unique obs: 2810 |
-
Processing
Software |
| ||||||||||||||||||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Refinement | Method to determine structure: ![]() Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
| ||||||||||||||||||||||||||||||||||||||||
Solvent computation | Shrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL | ||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso mean: 84.54 Å2 | ||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 3.6→47.21 Å
| ||||||||||||||||||||||||||||||||||||||||
Refine LS restraints |
| ||||||||||||||||||||||||||||||||||||||||
LS refinement shell |
| ||||||||||||||||||||||||||||||||||||||||
Refinement TLS params. | Method: refined / Origin x: -52.3876393731 Å / Origin y: 22.7845663519 Å / Origin z: 4.09307028667 Å
| ||||||||||||||||||||||||||||||||||||||||
Refinement TLS group | Selection details: all |