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Dictyostatin flexibility bridges conformations in solution and in the β-tubulin taxane binding site

Jogalekar, AS and Damodaran, K and Kriel, FH and Jung, WH and Alcaraz, AA and Zhong, S and Curran, DP and Snyder, JP (2011) Dictyostatin flexibility bridges conformations in solution and in the β-tubulin taxane binding site. Journal of the American Chemical Society, 133 (8). 2427 - 2436. ISSN 0002-7863

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Abstract

Dictyostatin (DCT, 1) is a complex, flexible polyketide macrolide that demonstrates potent microtubule-polymerization activity. Both a solution structure (2a) and a possible binding mode for DCT (Conf-1) have been proposed by earlier NMR experiments. In the present study, the conformational landscape of DCT in DMSO-d6 and methanol-d4 was explored using extensive force-field-based conformational searches combined with geometric parameters derived from solution NMR data. The results portray a diversity of conformations for dictyostatin that illustrates the molecule's flexibility and excludes the previously suggested dominant solution conformation 2a. One conformation present in DMSO-d6 with a 7% population (Conf-2, 0.6 kcal/mol above the global minimum at 298°) also satisfies the TR-NOESY NMR parameters of Canales et al. that characterize the taxane binding-site interaction between DCT and assembled microtubules in water. Application of several docking methods (Glide, Autodock, and RosettaLigand) has identified a low-energy binding model of the DCT/β-tubulin complex (Pose-2/Conf-2) that is gratifyingly compatible with the emerging DCT structure-activity data. © 2011 American Chemical Society.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Jogalekar, AS
Damodaran, K
Kriel, FH
Jung, WH
Alcaraz, AA
Zhong, S
Curran, DPcurran@pitt.eduCURRAN
Snyder, JP
Date: 2 March 2011
Date Type: Publication
Journal or Publication Title: Journal of the American Chemical Society
Volume: 133
Number: 8
Page Range: 2427 - 2436
DOI or Unique Handle: 10.1021/ja1023817
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0002-7863
MeSH Headings: Binding Sites; Bridged Compounds--chemistry; Macrolides--chemistry; Magnetic Resonance Spectroscopy; Models, Molecular; Molecular Conformation; Solutions; Tubulin--chemistry
PubMed ID: 21299225
Date Deposited: 08 Feb 2013 21:10
Last Modified: 12 Jun 2021 23:55
URI: http://d-scholarship-dev.library.pitt.edu/id/eprint/17235

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