› 7u8h

X-ray diffraction
1.7Å resolution

Discovery of a KRAS G12V Inhibitor in vivo Tool Compound starting from an HSQC-NMR based Fragment Hit

Released:
DOI: 10.2210/pdb7u8h/pdb
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PDB entry 7u8h coloured by chain, front view.
PDB entry 7u8h coloured by chain, side view.
PDB entry 7u8h coloured by chain, top view.
Source organism: Homo sapiens
Primary publication:
Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRASG12C Inhibitor.
Bröker J, Waterson AG, Smethurst C, Kessler D, Böttcher J, Mayer M, Gmaschitz G, Phan J, Little A, Abbott JR, Sun Q, Gmachl M, Rudolph D, Arnhof H, Rumpel K, Savarese F, Gerstberger T, Mischerikow N, Treu M, Herdeis L, Wunberg T, Gollner A, Weinstabl H, Mantoulidis A, Krämer O, McConnell DB, W Fesik S
OpenAccess logo J Med Chem (2022)
PMID: 36300829

Function and Biology Details

Reaction catalysed: 
GTP + H(2)O = GDP + phosphate
Biochemical function:
Biological process:
Cellular component:
Sequence domains:

Structure analysis Details

Assembly composition:
monomeric (preferred)
Assembly name:
PDBe Complex ID:
PDB-CPX-133991 (preferred)
Entry contents:
1 distinct polypeptide molecule
Macromolecule:
GTPase KRas, N-terminally processed Chains: A, B, C, D
Molecule details ›
Chains: A, B, C, D
Length: 170 amino acids
Theoretical weight: 19.37 KDa
Source organism: Homo sapiens
Expression system: Escherichia coli
UniProt:
  • Canonical: P01116 (Residues: 1-169; Coverage: 89%)
  • Best match: P01116-2 (Residues: 1-169)
Gene names: KRAS, KRAS2, RASK2
Sequence domains: Ras family

Ligands and Environments

4 bound ligands:
Ligand 2XO 4 x 2XO
Ligand GDP 4 x GDP
Ligand MG 4 x MG
Ligand LX6 2 x LX6
No modified residues

Experiments and Validation Details

wwPDB Validation report is not available for this entry.
X-ray source: APS BEAMLINE 21-ID-F
Spacegroup: C2221
Unit cell:
a: 94.835Å b: 98.48Å c: 149.888Å
α: 90° β: 90° γ: 90°
R-values:
R R work R free
0.174 0.172 0.199
Expression system: Escherichia coli

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Citations

4 review citations

Expanding Chemical Probe Space: Quality Criteria for Covalent and Degrader Probes.
Hartung et al. (2023)
3 more

2 mentions without citation

Fragment Optimization of Reversible Binding to the Switch II Pocket on KRAS Leads to a Potent, In Vivo Active KRASG12C Inhibitor.
Bröker et al. (2022)
1 more

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