9IM5

Tubulin-RB3(MUT)-TTL-Y12

This is a non-PDB format compatible entry.

Summary for 9IM5

• Entry DOI: 10.2210/pdb9im5/pdb
• Descriptor: Tubulin alpha-1B chain, ~{N}4-(1,3-benzodioxol-5-ylmethyl)-6-(1~{H}-indol-4-yl)pyrimidine-2,4-diamine, GUANOSINE-5'-DIPHOSPHATE, ... (13 entities in total)
• Functional Keywords: tubulin, cell cycle
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 6
• Total formula weight: 265317.16

Authors

Yan, W.,Yang, J.H. (deposition date: 2024-07-02, release date: 2025-02-26, Last modification date: 2025-03-26)

Primary citation

Li, Y.,Zhang, C.,Tang, D.,Wang, T.,Yan, W.,Yang, L.,Bai, P.,Tang, M.,Pei, H.,Chen, L.,Chen, Q.,Yang, J.
Identification of a ligand-binding site on tubulin mediating the tubulin-RB3 interaction.
Proc.Natl.Acad.Sci.USA, 122:e2424098122-e2424098122, 2025

PubMed Abstract: For decades, microtubules-composed of αβ-tubulin dimers-have been primary targets for cancer chemotherapy. While eight binding sites on the tubulin dimer have been structurally characterized, this study reveals a ninth. We found that the tubulin inhibitor Tumabulin-1 (TM1, a BML284 derivative) binds simultaneously to the well-known colchicine site and a previously unknown site, designated as Tumabulin site. This site resides at the interface of α1-tubulin, β1-tubulin, and RB3 within the tubulin-RB3-tubulintyrosine ligase complex. Remarkably, two TM1 molecules bind cooperatively to this relatively large pocket, interacting with all three proteins. Crucially, this binding is dependent on RB3; it is absent when RB3 is missing or the key residue H71 is mutated (H71Q). We further designed and synthesized Tumabulin-2 (TM2) that selectively binds the Tumabulin site, excluding binding the colchicine site. TM2 acts as a molecular glue, strengthening the interaction between RB3 and the tubulin dimer and consequently enhancing RB3's tubulin-depolymerizing activity. In conclusion, our findings confirm the existence of a ninth tubulin-binding site and offer a promising foundation for developing Tubulin-RB3 molecular glues as a next generation of anticancer therapeutics.

PubMed: 40067895
DOI: 10.1073/pnas.2424098122

Experimental method

X-RAY DIFFRACTION (2.86 Å)