24HT

Human KRAS G12D (GDP-bound) in complex with macrocyclic peptide inhibitor AP2527

This is a non-PDB format compatible entry.

Summary for 24HT

• Entry DOI: 10.2210/pdb24ht/pdb
• Descriptor: Isoform 2B of GTPase KRas, AP2527, GUANOSINE-5'-DIPHOSPHATE, ... (7 entities in total)
• Functional Keywords: kras, macrocyclic peptide, oncology, signaling protein, signaling protein-inhibitor complex
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 22405.58

Authors

Yamano, T.,Chiyoda, A.,Fukami, T.A.,Tanada, M.,Irie, M.,Torizawa, T. (deposition date: 2026-03-04, release date: 2026-05-27, Last modification date: 2026-07-01)

Primary citation

Chiyoda, A.,Matsuo, A.,Yamano, T.,Tanada, M.
Structure-Activity Relationship Analysis of Macrocyclic Peptide RAS Inhibitors: Spotlight on the Solvent-Exposed Region.
Acs Med.Chem.Lett., 17:1310-1315, 2026

PubMed Abstract: As ligand molecular weight increases, strategic structural optimization becomes increasingly important because larger ligands contain more modifiable atoms, making comprehensive exploration impractical. We present the structure-activity relationship (SAR) analysis of LUNA18 (paluratide, an 11-mer macrocyclic peptide RAS inhibitor) focusing on the amino acid side chains at position 5 in the solvent-exposed region. The analysis revealed that the contribution of position 5 to inhibitory activity depends on its local environment. Structural analysis identified two structural features: peptides forming a ″cavity″, which possess the hydrophobic interaction network among positions 1, 8, and 9, exhibited minimal changes upon position 5 modification, whereas those forming a ″groove″, lacking this interaction network, showed significant differences. These findings provide practical guidelines for optimizing macrocyclic peptides: evaluate the contributions of solvent-exposed side chain at key points and interpret SARs in the context of spatially proximal side chains.

PubMed: 42305191
DOI: 10.1021/acsmedchemlett.6c00122

Experimental method

X-RAY DIFFRACTION (1.7 Å)