9x53

Crystal structure of RhoGDI2 in complex with Compound HR3119

spinqualitylabelsall models 9x53, resolution 1.85Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9x53 is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.85Å Ligands: A1EY6, EDO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GDIR2_HUMAN Regulates the GDP/GTP exchange reaction of the Rho proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them. Publication Abstract from PubMed 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 HR3119 as the first ligand of RhoGDI2 with low-micromolar affinity (K(d) = 8 muM) starting from a millimolar binding affinity fragment hit (K(d) = 714 muM). HR3119 and its derivatives were rationally designed based on a series of ligand-bound RhoGDI2 crystal structures. HR3119 occupies the protein-protein interaction interface between RhoGDI2 and its endogenous ligand Rac1 to disrupt RhoGDI2-Rac1 binding. Interestingly, the complex structure suggests that (6R)-HR3119 preferentially bound to RhoGDI2 when crystallized with a racemic mixture. The purified (6R)-HR3119 demonstrated a nearly 100-fold binding affinity advantage compared to (6S)-HR3119. Finally, (6R)-HR3119 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. Fragment-Based Discovery of a Small-Molecule RhoGDI2 Ligand, HR3119, that Inhibits Cancer Cell Migration.,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 ACS Chem Biol. 2025 Oct 16. doi: 10.1021/acschembio.5c00361. PMID:41099476 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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