[English] 日本語
![](img/lk-miru.gif)
- PDB-9axm: Crystal structure of ARAF/MEK1 complex with NST-628 and a RAF dimer -
+
Open data
-
Basic information
Entry | Database: PDB / ID: 9axm | ||||||
---|---|---|---|---|---|---|---|
Title | Crystal structure of ARAF/MEK1 complex with NST-628 and a RAF dimer | ||||||
![]() |
| ||||||
![]() | ![]() ![]() ![]() | ||||||
Function / homology | ![]() epithelial cell proliferation involved in lung morphogenesis / positive regulation of endodermal cell differentiation / regulation of proteasomal ubiquitin-dependent protein catabolic process / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||
Biological species | ![]() ![]() | ||||||
Method | ![]() ![]() ![]() | ||||||
![]() | Quade, B. / Huang, X. | ||||||
Funding support | 1items
| ||||||
![]() | ![]() Title: The pan-RAF-MEK non degrading 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 / Aysegul Ozen / 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 / Aysegul Ozen / 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 is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents ...Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and is a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents 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 analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAFand 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 an areas of unmet patient need. | ||||||
History |
|
-
Structure visualization
Structure viewer | Molecule: ![]() ![]() |
---|
-
Downloads & links
-
Download
PDBx/mmCIF format | ![]() | 527 KB | Display | ![]() |
---|---|---|---|---|
PDB format | ![]() | Display | ![]() | |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
---|
-Related structure data
Related structure data | ![]() 9axaC ![]() 9axcC ![]() 9axhC ![]() 9axxC ![]() 9axyC ![]() 9ay7C ![]() 9ayaC C: citing same article ( |
---|---|
Similar structure data | Similarity search - Function & homology ![]() |
-
Links
-
Assembly
Deposited unit | ![]()
| ||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|
1 |
| ||||||||||||
Unit cell |
| ||||||||||||
Components on special symmetry positions |
|
-
Components
-Protein , 2 types, 4 molecules ACBD
#1: Protein | Mass: 34543.836 Da / Num. of mol.: 2 / Mutation: S218A S222A Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() References: UniProt: Q02750, ![]() #2: Protein | Mass: 31722.576 Da / Num. of mol.: 2 / Mutation: Y301D Y302D Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() ![]() References: UniProt: P10398, ![]() |
---|
-Non-polymers , 6 types, 127 molecules ![](data/chem/img/MG.gif)
![](data/chem/img/ANP.gif)
![](data/chem/img/EDO.gif)
![](data/chem/img/GOL.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/ANP.gif)
![](data/chem/img/EDO.gif)
![](data/chem/img/GOL.gif)
![](data/chem/img/HOH.gif)
#3: Chemical | Mass: 488.464 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H18F2N4O5S / Feature type: SUBJECT OF INVESTIGATION #4: Chemical | #5: Chemical | #6: Chemical | ChemComp-EDO / | ![]() #7: Chemical | ![]() #8: Water | ChemComp-HOH / | ![]() |
---|
-Details
Has ligand of interest | Y |
---|
-Experimental details
-Experiment
Experiment | Method: ![]() |
---|
-
Sample preparation
Crystal | Density Matthews: 2.46 Å3/Da / Density % sol: 50.07 % |
---|---|
Crystal grow![]() | Temperature: 291 K / Method: vapor diffusion, sitting drop / pH: 5.6 Details: 0.1M tri-sodium citrate pH 5.6, 20% 2-propanol, 20% PEG 4000 |
-Data collection
Diffraction | Mean temperature: 100 K / Serial crystal experiment: N |
---|---|
Diffraction source | Source: ![]() ![]() ![]() |
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![]() |
Reflection | Resolution: 2.42→47.46 Å / Num. obs: 50292 / % possible obs: 100 % / Redundancy: 13.6 % / Biso Wilson estimate: 51.83 Å2 / Rmerge(I) obs: 0.107 / Net I/σ(I): 17.7 |
Reflection shell | Resolution: 2.42→2.5 Å / Rmerge(I) obs: 1.179 / Num. unique obs: 4987 |
-
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: 70.28 Å2 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement step | Cycle: LAST / Resolution: 2.42→47.46 Å
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refine LS restraints |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
LS refinement shell |
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement TLS params. | Method: refined / Origin x: -7.77636963678 Å / Origin y: 58.5103975464 Å / Origin z: -23.3495734602 Å
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Refinement TLS group | Selection details: all |