8FPX

Crystal structure of tumor related RhoA mutant A161P in complex with GDP

Summary for 8FPX

• Entry DOI: 10.2210/pdb8fpx/pdb
• Related: 8FPW
• Descriptor: Transforming protein RhoA, GUANOSINE-5'-DIPHOSPHATE, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: small g proteins, gtpase, fast-cycling mutant, a161p, signaling protein, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 21160.17

Authors

Lin, Y.,Zheng, Y. (deposition date: 2023-01-05, release date: 2024-06-05, Last modification date: 2024-09-04)

Primary citation

Lin, Y.,Ramelot, T.A.,Senyuz, S.,Gursoy, A.,Jang, H.,Nussinov, R.,Keskin, O.,Zheng, Y.
Tumor-derived RHOA mutants interact with effectors in the GDP-bound state.
Nat Commun, 15:7176-7176, 2024

PubMed Abstract: RHOA mutations are found at diverse residues in various cancer types, implying mutation- and cell-specific mechanisms of tumorigenesis. Here, we focus on the underlying mechanisms of two gain-of-function RHOA mutations, A161P and A161V, identified in adult T-cell leukemia/lymphoma. We find that RHOA and RHOA are both fast-cycling mutants with increased guanine nucleotide dissociation/association rates compared with RHOA and show reduced GTP-hydrolysis activity. Crystal structures reveal an altered nucleotide association in RHOA and an open nucleotide pocket in RHOA. Both mutations perturb the dynamic properties of RHOA switch regions and shift the conformational landscape important for RHOA activity, as shown by P NMR and molecular dynamics simulations. Interestingly, RHOA and RHOA can interact with effectors in the GDP-bound state. H-N HSQC NMR spectra support the existence of an active population in RHOA-GDP. The distinct interaction mechanisms resulting from the mutations likely favor an RHOA-like "ON" conformation, endowing GDP-bound state effector binding activity.

PubMed: 39169042
DOI: 10.1038/s41467-024-51445-z

Experimental method

X-RAY DIFFRACTION (1.47 Å)