[English] 日本語
Yorodumi Papers
- Database of articles cited by EMDB/PDB/SASBDB data -

+
Search query

Keywords
Structure methods
Author
Journal
IF

-
Structure paper

TitleThe 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.
Journal, issue, pagesCancer Discov, Year 2024
Publish dateApr 8, 2024
AuthorsMeagan 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 /
PubMed AbstractAlterations 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.
External linksCancer Discov / PubMed:38588399
MethodsEM (single particle) / X-ray diffraction
Resolution2.07 - 4.36 Å
Structure data

43931

9axa

EMDB-43931, PDB-9axa:
CryoEM structure of activated CRAF/MEK/14-3-3 complex with NST-628
Method: EM (single particle) / Resolution: 4.36 Å

43932

9axc

EMDB-43932, PDB-9axc:
Activated CRAF/MEK heterotetramer from focused refinement of CRAF/MEK/14-3-3 complex
Method: EM (single particle) / Resolution: 4.16 Å

PDB-9axh:
Crystal structure of KSR1/MEK1 complex heterotetramer with NST-628
Method: X-RAY DIFFRACTION / Resolution: 2.81 Å

PDB-9axm:
Crystal structure of ARAF/MEK1 complex with NST-628 and a RAF dimer
Method: X-RAY DIFFRACTION / Resolution: 2.42 Å

PDB-9axx:
Crystal structure of BRAF/MEK1 complex with NST-628 and an active RAF dimer
Method: X-RAY DIFFRACTION / Resolution: 2.07 Å

PDB-9axy:
Crystal structure of BRAF/MEK complex with NST-628 and inactive RAF
Method: X-RAY DIFFRACTION / Resolution: 3.6 Å

PDB-9ay7:
Crystal structure of CRAF/MEK1 complex with NST-628 and inactive RAF
Method: X-RAY DIFFRACTION / Resolution: 2.41 Å

PDB-9aya:
Crystal structure of CRAF/MEK complex with NST-628 and active RAF dimer
Method: X-RAY DIFFRACTION / Resolution: 2.59 Å

Chemicals

PDB-1ahe:
ASPARTATE AMINOTRANSFERASE HEXAMUTANT

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

ChemComp-MG:
Unknown entry

ChemComp-EDO:
1,2-ETHANEDIOL / Ethylene glycol

ChemComp-CL:
Unknown entry / Chloride

ChemComp-HOH:
WATER / Water

ChemComp-GOL:
GLYCEROL / Glycerol

ChemComp-TRS:
2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / pH buffer*YM / Tris

ChemComp-NI:
NICKEL (II) ION / Nickel

ChemComp-ACT:
ACETATE ION / Acetate

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / Inhibitor / complex / SIGNALING PROTEIN

+
About Yorodumi Papers

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi Papers

Database of articles cited by EMDB/PDB/SASBDB data

  • Database of articles cited by EMDB, PDB, and SASBDB entries
  • Using PubMed data

Related info.:EMDB / PDB / SASBDB / Yorodumi / EMN Papers / Changes in new EM Navigator and Yorodumi

Read more