9X59
Crystal structure of RhoGDI2 in complex with Compound 2102
This is a non-PDB format compatible entry.
Summary for 9X59
| Entry DOI | 10.2210/pdb9x59/pdb |
| Descriptor | Rho GDP-dissociation inhibitor 2, (~{R})-(4-phenylphenyl)-thiophen-2-yl-methanamine (3 entities in total) |
| Functional Keywords | inhibitor, complex, rho gdp-dissociation inhibitor 2, signaling protein |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 16423.74 |
| Authors | |
| Primary citation | Liu, M.,Wan, S.,Guo, S.,Liu, J.,Li, W.,Wang, L.,Li, F.,Zhang, J.,Liu, X.,Liu, D.,Yao, X.,Gao, J.,Ruan, K.,He, W. Fragment-Based Discovery of a Small-Molecule RhoGDI2 Ligand, HR3119, that Inhibits Cancer Cell Migration. Acs Chem.Biol., 2025 Cited by PubMed Abstract: Guanine nucleotide dissociation inhibitors (GDIs) proteins, including RhoGDI2, regulate the functions of Ras superfamily proteins that are known to be important cancer drug targets. Given the challenges in directly targeting Ras superfamily proteins with small molecules, targeting GDIs represents a unique opportunity but has seen limited success. In this work, we discovered as the first ligand of RhoGDI2 with low-micromolar affinity ( = 8 μM) starting from a millimolar binding affinity fragment hit ( = 714 μM). and its derivatives were rationally designed based on a series of ligand-bound RhoGDI2 crystal structures. occupies the protein-protein interaction interface between RhoGDI2 and its endogenous ligand Rac1 to disrupt RhoGDI2-Rac1 binding. Interestingly, the complex structure suggests that (6)- preferentially bound to RhoGDI2 when crystallized with a racemic mixture. The purified (6)- demonstrated a nearly 100-fold binding affinity advantage compared to (6)-. Finally, (6)- engaged with RhoGDI2 in cells and suppressed the migration of aggressive breast cancer cells. Our work provides insights into the discovery of small-molecule compounds targeting RhoGDI2 in terms of methodology, chemistry starting points, compound design, and phenotype studies, underscoring exciting new perspectives in early drug discovery. PubMed: 41099476DOI: 10.1021/acschembio.5c00361 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.65 Å) |
Structure validation
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