PMID- 28207984
OWN - NLM
STAT- MEDLINE
DCOM- 20170623
LR  - 20190115
IS  - 1439-7633 (Electronic)
IS  - 1439-4227 (Print)
IS  - 1439-4227 (Linking)
VI  - 18
IP  - 10
DP  - 2017 May 18
TI  - Structural Basis of Microtubule Stabilization by Discodermolide.
PG  - 905-909
LID - 10.1002/cbic.201600696 [doi]
AB  - 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 beta-tubulin. The two compounds bind in a very similar hairpin 
      conformation, as previously observed in solution. However, they stabilize the 
      M-loop of beta-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 beta-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.
CI  - (c) 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.
FAU - Prota, Andrea E
AU  - Prota AE
AUID- ORCID: 0000-0003-0875-5339
AD  - Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul 
      Scherrer Institut, OFLC/111, 5232, Villigen PSI, Switzerland.
FAU - Bargsten, Katja
AU  - Bargsten K
AD  - Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul 
      Scherrer Institut, OFLC/111, 5232, Villigen PSI, Switzerland.
AD  - Current address: Department of Biochemistry, University of Zurich, 
      Winterthurerstrasse 190, 8057, Zurich, Switzerland.
FAU - Redondo-Horcajo, Mariano
AU  - Redondo-Horcajo M
AUID- ORCID: 0000-0002-9329-4786
AD  - Chemical and Physical Biology, Centro de Investigaciones Biologicas, Consejo 
      Superior de Investigaciones Cientificas CIB-CSIC, Ramiro de Maeztu 9, 28040, 
      Madrid, Spain.
FAU - Smith, Amos B 3rd
AU  - Smith AB 3rd
AD  - Department of Chemistry, University of Pennsylvania, 231 S. 34th Street, 
      Philadelphia, PA, 19104, USA.
FAU - Yang, Chia-Ping H
AU  - Yang CH
AD  - Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 
      Morris Park Avenue, Golding 201, Bronx, NY, 1046, USA.
FAU - McDaid, Hayley M
AU  - McDaid HM
AD  - Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 
      Morris Park Avenue, Golding 201, Bronx, NY, 1046, USA.
FAU - Paterson, Ian
AU  - Paterson I
AD  - University Chemical Laboratory, Cambridge University, Lensfield Road, Cambridge, 
      CB2 1EW, UK.
FAU - Horwitz, Susan B
AU  - Horwitz SB
AD  - Department of Molecular Pharmacology, Albert Einstein College of Medicine, 1300 
      Morris Park Avenue, Golding 201, Bronx, NY, 1046, USA.
FAU - Fernando Diaz, Jose
AU  - Fernando Diaz J
AUID- ORCID: 0000-0003-2743-3319
AD  - Chemical and Physical Biology, Centro de Investigaciones Biologicas, Consejo 
      Superior de Investigaciones Cientificas CIB-CSIC, Ramiro de Maeztu 9, 28040, 
      Madrid, Spain.
FAU - Steinmetz, Michel O
AU  - Steinmetz MO
AD  - Laboratory of Biomolecular Research, Department of Biology and Chemistry, Paul 
      Scherrer Institut, OFLC/111, 5232, Villigen PSI, Switzerland.
LA  - eng
GR  - R01 CA077263/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20170327
PL  - Germany
TA  - Chembiochem
JT  - Chembiochem : a European journal of chemical biology
JID - 100937360
RN  - 0 (Alkanes)
RN  - 0 (Bridged-Ring Compounds)
RN  - 0 (Carbamates)
RN  - 0 (Lactones)
RN  - 0 (Pyrones)
RN  - 0 (Taxoids)
RN  - 0 (Tubulin)
RN  - 0 (Tubulin Modulators)
RN  - 1605-68-1 (taxane)
RN  - DHG59994DN (discodermolide)
SB  - IM
MH  - Alkanes/*chemistry/metabolism
MH  - Binding Sites
MH  - Bridged-Ring Compounds/*chemistry/metabolism
MH  - Carbamates/*chemistry/metabolism
MH  - Crystallography, X-Ray
MH  - Humans
MH  - Lactones/*chemistry/metabolism
MH  - Microtubules/*metabolism
MH  - Pyrones/*chemistry/metabolism
MH  - Taxoids/*chemistry/metabolism
MH  - Tubulin/*chemistry/metabolism
MH  - Tubulin Modulators/*chemistry/metabolism
PMC - PMC5559732
MID - NIHMS889374
OTO - NOTNLM
OT  - X-ray crystallography
OT  - drug design
OT  - microtubules
OT  - molecular mechanism of action
OT  - structure elucidation
EDAT- 2017/02/17 06:00
MHDA- 2017/06/24 06:00
PMCR- 2018/05/18
CRDT- 2017/02/17 06:00
PHST- 2016/12/27 00:00 [received]
PHST- 2017/02/17 06:00 [pubmed]
PHST- 2017/06/24 06:00 [medline]
PHST- 2017/02/17 06:00 [entrez]
PHST- 2018/05/18 00:00 [pmc-release]
AID - 10.1002/cbic.201600696 [doi]
PST - ppublish
SO  - Chembiochem. 2017 May 18;18(10):905-909. doi: 10.1002/cbic.201600696. Epub 2017 
      Mar 27.