Identification of the clinical development candidate MRTX849, a covalent KRASG12C inhibitor for the treatment of cancer

Structure

x-ray diffraction · 3 distinct chains · 37% helix, 25% strand (DSSP).

Ligands and binding sites

• GDP · Guanosine-5'-diphosphate · ligand · 4 copies · chains A, B, C, D
• M1X · {(2S)-4-[7-(8-chloronaphthalen-1-yl)-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-yl]-1-[(2S)-2-fluoropropanoyl]piperazin-2-yl}acetonitrile · ligand · 4 copies · chains A, B, C, D
• MG · Magnesium ion · metal · 4 copies · chains A, B, C, D

Binding sites are the residues within 4.5 Å of a ligand's heavy atoms.

Pockets

7 pockets found on a 1 Å grid, 6 with a druggability of 0.5 or more.

Interfaces

5 interfaces between chains.

• B–D · 575 Ų buried · 12 hydrogen bonds · protein-protein
• A–C · 430 Ų buried · 6 hydrogen bonds · protein-protein
• A–B · 217 Ų buried · 3 hydrogen bonds · protein-protein
• C–D · 123 Ų buried · 1 hydrogen bond · protein-protein
• B–C · 62 Ų buried · 0 hydrogen bonds · protein-protein

Modifications

Observed in the structure: 4 covalent (covalent ligand).

Compared structures

• 6UT0 · Identification of the Clinical Development Candidate MRTX849, a Covalent KRASG12C… · the same entry in another collection · chain A against A, TM-score 1.00

Analyse

• Open in the research workbench: secondary structure, accessibility, pockets, interfaces, conservation, variants, modifications, peptides and crosslinks on the 3D structure
• Every structure of UniProt P01116
• Elsewhere: RCSB PDB 6UT0 · PDBe 6UT0 · UniProt P01116