9VNH
Structure of wild-type RhoA in complex with GDP and magnesium ion
Summary for 9VNH
| Entry DOI | 10.2210/pdb9vnh/pdb |
| Descriptor | Transforming protein RhoA, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | small gtpase, rhoa, wild-type, gdp bound, cell invasion |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 20992.02 |
| Authors | |
| Primary citation | Wu, H.,Liu, Z.,Jiang, H.,Zhao, H.,Dong, C.,Lu, Y.,Zu, S.,Guo, Y.,Lai, C.,Luo, P.,Xu, K.,Yang, Y.,Yang, Y.,Sun, Z.,Huang, Q.,Xiong, H.,Zhou, L.,Luo, Y.,Zeng, Y.,Du, D.,Liang, Z.,Xiao, W.,Zhao, S.,Zhang, W.,Tang, Y.,Xiao, C.,Chen, K.,Yang, X.,Wang, F.,Luo, C. Discovering Targetable Conformation of RhoA Mutant by Integrating Native Mass Spectrometry, Ultraviolet Photodissociation, and X-ray Diffraction. J.Am.Chem.Soc., 2026 Cited by PubMed Abstract: Pathogenic mutations in "undruggable" Ras superfamily proteins challenge drug development by inducing subtle, dynamic conformational changes. Here, we integrated X-ray crystallography with native mass spectrometry and ultraviolet photodissociation (nMS-UVPD) to reveal a cryptic conformation in the oncogenic Y42C mutant of RhoA. While crystallography alone resolved two ambiguous structures, nMS-UVPD determined the dominant conformation by directly mapping the mutant's conformational dynamics, identifying an enhanced Mg-locked conformation. We explored the mechanism of mutation impairing GTP hydrolysis. This state unmasks a previously hidden, druggable pocket adjacent to Cys42, guiding our identification of a covalent inhibitor. Our integrated approach establishes a roadmap for targeting pathogenic protein mutants previously considered "undruggable" due to their highly dynamic nature. PubMed: 41837560DOI: 10.1021/jacs.5c20067 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.79 Å) |
Structure validation
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