Crystal Structure of a Human K-Ras G12D Mutant in Complex with GDP and the Cyclic Inhibitory Peptide KRpep-2d
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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.
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The crystal structure of KRASG12D-GDP with KRpep-2d showed that this KRASG12D-selective inhibitory peptide binds near switch 2 and competes with GEF binding.
“By contrast, the crystal structure of KRASG12D-GDP in a complex with KRpep-2d revealed that this KRASG12D-selective inhibitory peptide binds to a region near switch 2 and competes with GEF binding175.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [175]
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- Authors
- Sogabe, S., Kamada, Y., Miwa, M., Niida, A., Sameshima, T., Kamaura, M., Yonemori, K., Sasaki, S., Sakamoto, J.-I., & Sakamoto, K.
- Affiliations
- Takeda (Japan) (JP)
- Corresponding author
- Sogabe, Satoshi
- Sakamoto, Kotaro
- Venue
- ACS Medicinal Chemistry Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-05-15
- Volume
- 8
- Issue
- 7
- Pages
- 732-736
- ISSN
- 1948-5875 (ISSN-L)
- PMC
- PMC5512123
- OpenAlex
- W2612770567
- Cited by
- 83
- References
- 25
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 11 · 2023: 6 · 2022: 11 · 2021: 6 · 2020: 14 · 2019: 11 · 2018: 4
- FWCI
- 3.22
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- ACS Medicinal Chemistry Letters (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- GDP binding, switch II, allosteric inhibition, guanine nucleotide exchange factor, cancer therapy targets
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