RCSB PDB - 9AYA: Crystal structure of CRAF/MEK complex with NST-628 and active RAF dimer

 9AYA

Crystal structure of CRAF/MEK complex with NST-628 and active RAF dimer


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.59 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 

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Literature

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.

Ryan, M.B.Quade, B.Schenk, N.Fang, Z.Zingg, M.Cohen, S.E.Swalm, B.M.Li, C.Ozen, A.Ye, C.Ritorto, M.S.Huang, X.Dar, A.C.Han, Y.Hoeflich, K.P.Hale, M.Hagel, M.

(2024) Cancer Discov 14: 1190-1205

  • DOI: https://doi.org/10.1158/2159-8290.CD-24-0139
  • Primary Citation of Related Structures:  
    9AXA, 9AXC, 9AXH, 9AXM, 9AXX, 9AXY, 9AY7, 9AYA

  • PubMed 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 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.


  • Organizational Affiliation

    Nested Therapeutics, Cambridge, MA, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RAF proto-oncogene serine/threonine-protein kinase
A, C
280Homo sapiensMutation(s): 2 
Gene Names: RAF1RAF
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for P04049 (Homo sapiens)
Explore P04049 
Go to UniProtKB:  P04049
PHAROS:  P04049
GTEx:  ENSG00000132155 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04049
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Dual specificity mitogen-activated protein kinase kinase 1
B, D
310Homo sapiensMutation(s): 2 
Gene Names: MAP2K1MEK1PRKMK1
EC: 2.7.12.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q02750 (Homo sapiens)
Explore Q02750 
Go to UniProtKB:  Q02750
PHAROS:  Q02750
GTEx:  ENSG00000169032 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ02750
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
ANP
Query on ANP

Download Ideal Coordinates CCD File 
F [auth B],
I [auth D]
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER
C10 H17 N6 O12 P3
PVKSNHVPLWYQGJ-KQYNXXCUSA-N
A1AHE (Subject of Investigation/LOI)
Query on A1AHE

Download Ideal Coordinates CCD File 
E [auth B],
H [auth D]
N-[3-fluoro-4-({7-[(3-fluoropyridin-2-yl)oxy]-4-methyl-2-oxo-2H-1-benzopyran-3-yl}methyl)pyridin-2-yl]-N'-methylsulfuric diamide
C22 H18 F2 N4 O5 S
YQSZJOABXRROQR-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
G [auth B],
J [auth D]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.59 Å
  • R-Value Free: 0.257 
  • R-Value Work: 0.212 
  • R-Value Observed: 0.214 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 149.725α = 90
b = 58.202β = 95.59
c = 162.347γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XDSdata scaling
PHASERphasing
REFMACrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 

Created with Raphaël 2.3.0Worse 01 BetterLigand structure goodness of fit to experimental dataBest fitted A1AHEClick on this verticalbar to view details

Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2024-04-17
    Type: Initial release
  • Version 1.1: 2024-07-10
    Changes: Database references