Oncogenic mutations Q61L and Q61H confer active form-like structural features to the inactive state (state 1) conformation of H-Ras protein
| Autor: | Ryo Miyamoto, Takashi Kumasaka, Shigeyuki Matsumoto, Tohru Kataoka, Takashi Kawamura, Mitsugu Araki, Fumi Shima, Haruka Taniguchi-Tamura, Chiemi Tsuda, Yasushi Okuno |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Mutant Molecular Conformation Biophysics Guanosine Oncogenic mutant Crystal structure Crystallography X-Ray medicine.disease_cause Biochemistry Proto-Oncogene Proteins p21(ras) 03 medical and health sciences Molecular dynamics chemistry.chemical_compound Residue (chemistry) 0302 clinical medicine Molecular dynamics simulation medicine Humans Molecular Biology X-ray crystallography Mutation Chemistry Cell Biology State transition 030104 developmental biology 030220 oncology & carcinogenesis Intramolecular force Guanosine Triphosphate Structural communication Ras |
| Zdroj: | Biochemical and Biophysical Research Communications. 565:85-90 |
| ISSN: | 0006-291X |
| Popis: | GTP-bound forms of Ras proteins (Ras•GTP) assume two interconverting conformations, "inactive" state 1 and "active" state 2. Our previous study on the crystal structure of the state 1 conformation of H-Ras in complex with guanosine 5'-(β, γ-imido)triphosphate (GppNHp) indicated that state 1 is stabilized by intramolecular hydrogen-bonding interactions formed by Gln61. Since Ras are constitutively activated by substitution mutations of Gln61, here we determine crystal structures of the state 1 conformation of H-Ras•GppNHp carrying representative mutations Q61L and Q61H to observe the effect of the mutations. The results show that these mutations alter the mode of hydrogen-bonding interactions of the residue 61 with Switch II residues and induce conformational destabilization of the neighboring regions. In particular, Q61L mutation results in acquirement of state 2-like structural features. Moreover, the mutations are likely to impair an intramolecular structural communication between Switch I and Switch II. Molecular dynamics simulations starting from these structures support the above observations. These findings may give a new insight into the molecular mechanism underlying the aberrant activation of the Gln61 mutants. |
| Databáze: | OpenAIRE |
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