Crystal Structure of a Human K-Ras G12D Mutant in Complex with GDP and the Cyclic Inhibitory Peptide KRpep-2d
| Autor: | Satoshi Sogabe, Ayumu Niida, Tomoya Sameshima, Kazuko Yonemori, Junichi Sakamoto, Masanori Miwa, Shigekazu Sasaki, Kotaro Sakamoto, Yusuke Kamada, Masahiro Kamaura |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Protein family Organic Chemistry Mutant Peptide Crystal structure Biology Biochemistry Protein–protein interaction Amino acid 03 medical and health sciences 030104 developmental biology chemistry Drug Discovery Inhibitory peptide Guanine nucleotide exchange factor |
| Zdroj: | ACS Medicinal Chemistry Letters. 8:732-736 |
| ISSN: | 1948-5875 |
| DOI: | 10.1021/acsmedchemlett.7b00128 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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