title: Structural Basis of Microtubule Stabilization by Discodermolide.
abstract: Microtubule-stabilizing agents (MSAs) are widely used in chemotherapy. Using X-ray crystallography we elucidated the detailed binding modes of two potent MSAs, (+)-discodermolide (DDM) and the DDM-paclitaxel hybrid KS-1-199-32, in the taxane pocket of β-tubulin. The two compounds bind in a very similar hairpin conformation, as previously observed in solution. However, they stabilize the M-loop of β-tubulin differently: KS-1-199-32 induces an M-loop helical conformation that is not observed for DDM. In the context of the microtubule structure, both MSAs connect the β-tubulin helices H6 and H7 and loop S9-S10 with the M-loop. This is similar to the structural effects elicited by epothilone A, but distinct from paclitaxel. Together, our data reveal differential binding mechanisms of DDM and KS-1-199-32 on tubulin.
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, OFLC/111, 5232, Villigen PSI, Switzerland.
authors.forename: Andrea E
authors.identifier: 0000-0003-0875-5339
authors.initials: AE
authors.lastname: Prota
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, OFLC/111, 5232, Villigen PSI, Switzerland.|Current address: Department of Biochemistry, University of Zürich, Winterthurerstrasse 190, 8057, Zürich, Switzerland.
authors.forename: Katja
authors.initials: K
authors.lastname: Bargsten
authors.affiliation: Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas CIB-CSIC, Ramiro de Maeztu 9, 28040, Madrid, Spain.
authors.forename: Mariano
authors.identifier: 0000-0002-9329-4786
authors.initials: M
authors.lastname: Redondo-Horcajo
authors.affiliation: Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, Philadelphia, PA, 19104, USA.
authors.forename: Amos B
authors.initials: AB
authors.lastname: Smith
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Golding 201, Bronx, NY, 1046, USA.
authors.forename: Chia-Ping H
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Golding 201, Bronx, NY, 1046, USA.
authors.forename: Hayley M
authors.initials: HM
authors.lastname: McDaid
authors.affiliation: University Chemical Laboratory, Cambridge University, Lensfield Road, Cambridge, CB2 1EW, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Paterson
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Golding 201, Bronx, NY, 1046, USA.
authors.forename: Susan B
authors.initials: SB
authors.lastname: Horwitz
authors.affiliation: Chemical and Physical Biology, Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas CIB-CSIC, Ramiro de Maeztu 9, 28040, Madrid, Spain.
authors.forename: José
authors.identifier: 0000-0003-2743-3319
authors.initials: J
authors.lastname: Fernando Díaz
authors.affiliation: Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul Scherrer Institut, OFLC/111, 5232, Villigen PSI, Switzerland.
authors.forename: Michel O
authors.initials: MO
authors.lastname: Steinmetz
mesh_terms: D000473:Alkanes / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D001952:Bridged-Ring Compounds / Q000737:chemistry* / Q000378:metabolism; D002219:Carbamates / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D007783:Lactones / Q000737:chemistry* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism*; D011753:Pyrones / Q000737:chemistry* / Q000378:metabolism; D043823:Taxoids / Q000737:chemistry* / Q000378:metabolism; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000473:Alkanes; D001952:Bridged-Ring Compounds; D002219:Carbamates; D007783:Lactones; D011753:Pyrones; D043823:Taxoids; D014404:Tubulin; D050257:Tubulin Modulators; C080625:taxane; C071229:discodermolide
keywords: X-ray crystallography; drug design; microtubules; molecular mechanism of action; structure elucidation