The Unique Binding Mode of Laulimalide to Two Tubulin Protofilaments.
Laulimalide, a cancer chemotherapeutic in preclinical development, has a unique binding site located on two adjacent β-tubulin units between tubulin protofilaments of a microtubule. Our extended protein model more accurately mimics the microtubule environment, and together with a 135 ns molecular dynamics simulation, identifies a new binding mode for laulimalide, which differs from the modes presented in work using smaller protein models. The new laulimalide-residue interactions that are computationally revealed explain the contacts observed via independent mass shift perturbation experiments. The inclusion of explicit solvent shows that many laulimalide-tubulin interactions are water mediated. The new contacts between the drug and the microtubule structure not only improve our understanding of laulimalide binding but also will be essential for efficient derivatization and optimization of this prospective cancer chemotherapy agent. Observed changes in secondary protein structure implicate the S7-H9 loop (M-loop) and H1'-S2 loop in the mechanism by which laulimalide stabilizes microtubules to exert its cytotoxic effects.
Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, AB, T6G 2G2, Canada.
Cassandra D M
CD
Churchill
Department of Chemistry, University of Alberta, 11227 Saskatchewan Drive, Edmonton, AB, T6G 2G2, Canada.
Mariusz
M
Klobukowski
Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, AB, T6G 1Z2, Canada.|Department of Physics, University of Alberta, 4-181 CCIS, Edmonton, AB, T6G 2E1, Canada.
Jack A
JA
Tuszynski
D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D055808:Drug Discovery / Q000379:methods; D018942:Macrolides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D008870:Microtubules / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D056004:Molecular Dynamics Simulation; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
D000970:Antineoplastic Agents; D018942:Macrolides; D014404:Tubulin; D050257:Tubulin Modulators; C117305:laulimalide
drug discovery; molecular modeling; natural product; receptor and ligands