5XCO

Crystal structure of human K-Ras G12D Mutant in complex with GDP and Cyclic Inhibitory Peptide

Summary for 5XCO

• Entry DOI: 10.2210/pdb5xco/pdb
• Descriptor: GTPase KRas, ACE-ARG-ARG-ARG-ARG-CYS-PRO-LEU-TYR-ILE-SER-TYR-ASP-PRO-VAL-CYS-ARG-ARG-ARG-ARG-NH2, GUANOSINE-5'-DIPHOSPHATE, ... (5 entities in total)
• Functional Keywords: hydrolase, complex, inhibitor, small gtpase, oncogene, signaling, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human); More
• Cellular location: Cell membrane ; Lipid-anchor ; Cytoplasmic side : P01116
• Total number of polymer chains: 2
• Total formula weight: 22533.28

Authors

Sogabe, S.,Miwa, M. (deposition date: 2017-03-23, release date: 2017-05-24, Last modification date: 2024-10-23)

Primary citation

Sogabe, S.,Kamada, Y.,Miwa, M.,Niida, A.,Sameshima, T.,Kamaura, M.,Yonemori, K.,Sasaki, S.,Sakamoto, J.,Sakamoto, K.
Crystal Structure of a Human K-Ras G12D Mutant in Complex with GDP and the Cyclic Inhibitory Peptide KRpep-2d
ACS Med Chem Lett, 8:732-736, 2017

PubMed Abstract: The Ras proteins play roles in cell differentiation, proliferation, and survival. Aberrant signaling through Ras-mediated pathways in tumor cells occurs as a result of several types of mutational damage, which most frequently affects the amino acids G12, G13, and Q61. Recently, KRpep-2d was identified as a K-Ras(G12D) selective inhibitory peptide against the G12D mutant of K-Ras, which is a key member of the Ras protein family and an attractive cancer therapeutic target. In this study, the crystal structure of the human K-Ras(G12D) mutant was determined in complex with GDP and KRpep-2d at 1.25 Å resolution. This structure revealed that the peptide binds near Switch II and allosterically blocks protein-protein interactions with the guanine nucleotide exchange factor. This discovery of a unique binding pocket provides valuable information that will facilitate the design of direct Ras inhibitors.

PubMed: 28740607
DOI: 10.1021/acsmedchemlett.7b00128

Experimental method

X-RAY DIFFRACTION (1.25 Å)