PMID- 24470331
OWN - NLM
STAT- MEDLINE
DCOM- 20140929
LR  - 20161125
IS  - 1521-3773 (Electronic)
IS  - 1433-7851 (Linking)
VI  - 53
IP  - 6
DP  - 2014 Feb 3
TI  - Structural basis of microtubule stabilization by laulimalide and peloruside A.
PG  - 1621-5
LID - 10.1002/anie.201307749 [doi]
AB  - Laulimalide and peloruside A are microtubule-stabilizing agents (MSAs), the 
      mechanism of action on microtubules of which is poorly defined. Here, using X-ray 
      crystallography it is shown that laulimalide and peloruside A bind to a unique 
      non-taxane site on beta-tubulin and use their respective macrolide core structures 
      to interact with a second tubulin dimer across protofilaments. At the same time, 
      they allosterically stabilize the taxane-site M-loop that establishes lateral 
      tubulin contacts in microtubules. Structures of ternary complexes of tubulin with 
      laulimalide/peloruside A and epothilone A are also solved, and a crosstalk 
      between the laulimalide/peloruside and taxane sites via the M-loop of beta-tubulin 
      is found. Together, the data define the mechanism of action of laulimalide and 
      peloruside A on tubulin and microtubules. The data further provide a structural 
      framework for understanding the synergy observed between two classes of MSAs in 
      tubulin assembly and the inhibition of cancer cell growth.
CI  - Copyright (c) 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
FAU - Prota, Andrea E
AU  - Prota AE
AD  - Department of Biology and Chemistry, Laboratory of Biomolecular Research, Paul 
      Scherrer Institut, 5232 Villigen PSI (Switzerland).
FAU - Bargsten, Katja
AU  - Bargsten K
FAU - Northcote, Peter T
AU  - Northcote PT
FAU - Marsh, May
AU  - Marsh M
FAU - Altmann, Karl-Heinz
AU  - Altmann KH
FAU - Miller, John H
AU  - Miller JH
FAU - Diaz, Jose Fernando
AU  - Diaz JF
FAU - Steinmetz, Michel O
AU  - Steinmetz MO
LA  - eng
SI  - PDB/404H
SI  - PDB/404I
SI  - PDB/404J
SI  - PDB/404L
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140127
PL  - Germany
TA  - Angew Chem Int Ed Engl
JT  - Angewandte Chemie (International ed. in English)
JID - 0370543
RN  - 0 (Bridged Bicyclo Compounds, Heterocyclic)
RN  - 0 (Lactones)
RN  - 0 (Macrolides)
RN  - 0 (Tubulin)
RN  - 0 (laulimalide)
RN  - 0 (peloruside A)
SB  - IM
MH  - Allosteric Regulation
MH  - Binding Sites
MH  - Bridged Bicyclo Compounds, Heterocyclic/*chemistry/metabolism
MH  - Crystallography, X-Ray
MH  - Dimerization
MH  - Humans
MH  - Lactones/*chemistry/metabolism
MH  - Macrolides/*chemistry/metabolism
MH  - Molecular Dynamics Simulation
MH  - Protein Binding
MH  - Protein Structure, Tertiary
MH  - Tubulin/chemistry/*metabolism
OTO - NOTNLM
OT  - X-ray crystallography
OT  - drug discovery
OT  - microtubules
OT  - molecular mechanism of action
OT  - structure elucidation
EDAT- 2014/01/29 06:00
MHDA- 2014/09/30 06:00
CRDT- 2014/01/29 06:00
PHST- 2013/09/03 00:00 [received]
PHST- 2013/11/28 00:00 [revised]
PHST- 2014/01/29 06:00 [entrez]
PHST- 2014/01/29 06:00 [pubmed]
PHST- 2014/09/30 06:00 [medline]
AID - 10.1002/anie.201307749 [doi]
PST - ppublish
SO  - Angew Chem Int Ed Engl. 2014 Feb 3;53(6):1621-5. doi: 10.1002/anie.201307749. 
      Epub 2014 Jan 27.