Rotational-echo double-resonance NMR distance measurements for the tubulin-bound Paclitaxel conformation.
The important anticancer drug Taxol (paclitaxel, PTX) owes its unique activity to its ability to bind to tubulin in a stoichiometric ratio and promote its assembly into microtubules. The conformation of the microtubule-bound drug has been the focus of numerous research efforts, since the inability of polymerized tubulin to form crystals precludes structure proof by X-ray crystallography. Likewise, although the alpha,beta-tubulin dimer structure has been solved by electron crystallography, the 3.7 A resolution is too low to permit direct determination of either ligand conformation or binding pose. In this article, we present experimental results from 2H{19F} REDOR NMR that provide direct confirmation that paclitaxel adopts a T-shaped conformation when it is bound to tubulin.
Paik
Younkee
Y
Department of Chemistry, M/C 0212, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061, USA.
Yang
Chao
C
Metaferia
Belhu
B
Tang
Shoubin
S
Bane
Susan
S
Ravindra
Rudravajhala
R
Shanker
Natasha
N
Alcaraz
Ana A
AA
Johnson
Scott A
SA
Schaefer
Jacob
J
O'Connor
Robert D
RD
Cegelski
Lynette
L
Snyder
James P
JP
Kingston
David G I
DG
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy / Q000379:methods*; D008958:Models, Molecular; D008968:Molecular Conformation; D017239:Paclitaxel / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D012399:Rotation; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014404:Tubulin / Q000737:chemistry*
D008024:Ligands; D014404:Tubulin; D017239:Paclitaxel