4TUY

Tubulin-Rhizoxin complex

Summary for 4TUY

• Entry DOI: 10.2210/pdb4tuy/pdb
• Related: 4I4T 4I50 4I55 4IHJ 4IIJ 4O2A 4O2B 4O4H 4O4I 4O4J 4O4L
• Descriptor: Tubulin alpha-1B chain, (1R,2R,3E,5R,7R,8S,10S,13E,16R)-8-hydroxy-10-[(2S,3R,4E,6E,8E)-3-methoxy-4,8-dimethyl-9-(2-methyl-1,3-oxazol-4-yl)nona-4,6,8-trien-2-yl]-2,7-dimethyl-6,11,19-trioxatricyclo[14.3.1.0~5,7~]icosa-3,13-diene-12,18-dione, PHOSPHOMETHYLPHOSPHONIC ACID ADENYLATE ESTER, ... (12 entities in total)
• Functional Keywords: cell cycle, cytoskeleton, tubulin fold, rhizoxin
• Biological source: Rattus norvegicus (Rat); More
• Cellular location: Cytoplasm, cytoskeleton: P81947; Cytoplasm, cytoskeleton (By similarity): Q6B856; Golgi apparatus: P63043
• Total number of polymer chains: 6
• Total formula weight: 265075.96

Authors

Prota, A.E.,Bargsten, K.,Diaz, J.F.,Marsh, M.,Cuevas, C.,Liniger, M.,Neuhaus, C.,Andreu, J.M.,Altmann, K.H.,Steinmetz, M.O. (deposition date: 2014-06-25, release date: 2014-08-27, Last modification date: 2023-12-20)

Primary citation

Prota, A.E.,Bargsten, K.,Diaz, J.F.,Marsh, M.,Cuevas, C.,Liniger, M.,Neuhaus, C.,Andreu, J.M.,Altmann, K.H.,Steinmetz, M.O.
A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugs.
Proc.Natl.Acad.Sci.USA, 111:13817-13821, 2014

PubMed Abstract: The recent success of antibody-drug conjugates (ADCs) in the treatment of cancer has led to a revived interest in microtubule-destabilizing agents. Here, we determined the high-resolution crystal structure of the complex between tubulin and maytansine, which is part of an ADC that is approved by the US Food and Drug Administration (FDA) for the treatment of advanced breast cancer. We found that the drug binds to a site on β-tubulin that is distinct from the vinca domain and that blocks the formation of longitudinal tubulin interactions in microtubules. We also solved crystal structures of tubulin in complex with both a variant of rhizoxin and the phase 1 drug PM060184. Consistent with biochemical and mutagenesis data, we found that the two compounds bound to the same site as maytansine and that the structures revealed a common pharmacophore for the three ligands. Our results delineate a distinct molecular mechanism of action for the inhibition of microtubule assembly by clinically relevant agents. They further provide a structural basis for the rational design of potent microtubule-destabilizing agents, thus opening opportunities for the development of next-generation ADCs for the treatment of cancer.

PubMed: 25114240
DOI: 10.1073/pnas.1408124111

Experimental method

X-RAY DIFFRACTION (2.1 Å)