The binding mode of side chain- and C3-modified epothilones to tubulin

Erdélyi, Máté; Navarro-Vázquez, Armando; Pfeiffer, Bernhard; Kuzniewski, Christian N; Felser, Andrea; Widmer, Toni; Gertsch, Jürg; Pera, Benet; Díaz, José Fernando; Altmann, Karl-Heinz; Carlomagno, Teresa (2010). The binding mode of side chain- and C3-modified epothilones to tubulin. ChemMedChem, 5(6), pp. 911-920. Weinheim: Wiley-VCH 10.1002/cmdc.201000050

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The tubulin-binding mode of C3- and C15-modified analogues of epothilone A (Epo A) was determined by NMR spectroscopy and computational methods and compared with the existing structural models of tubulin-bound natural Epo A. Only minor differences were observed in the conformation of the macrocycle between Epo A and the C3-modified analogues investigated. In particular, 3-deoxy- (compound 2) and 3-deoxy-2,3-didehydro-Epo A (3) were found to adopt similar conformations in the tubulin-binding cleft as Epo A, thus indicating that the 3-OH group is not essential for epothilones to assume their bioactive conformation. None of the available models of the tubulin-epothilone complex is able to fully recapitulate the differences in tubulin-polymerizing activity and microtubule-binding affinity between C20-modified epothilones 6 (C20-propyl), 7 (C20-butyl), and 8 (C20-hydroxypropyl). Based on the results of transferred NOE experiments in the presence of tubulin, the isomeric C15 quinoline-based Epo B analogues 4 and 5 show very similar orientations of the side chain, irrespective of the position of the nitrogen atom in the quinoline ring. The quinoline side chain stacks on the imidazole moiety of beta-His227 with equal efficiency in both cases, thus suggesting that the aromatic side chain moiety in epothilones contributes to tubulin binding through strong van der Waals interactions with the protein rather than hydrogen bonding involving the heteroaromatic nitrogen atom. These conclusions are in line with existing tubulin polymerization and microtubule-binding data for 4, 5, and Epo B.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Gertsch, Jürg

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1860-7179

Publisher:

Wiley-VCH

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:12

Last Modified:

27 Jun 2014 14:29

Publisher DOI:

10.1002/cmdc.201000050

PubMed ID:

20432490

Web of Science ID:

000278969200013

URI:

https://boris.unibe.ch/id/eprint/2438 (FactScience: 204937)

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