PDBsum entry: 1z2b

Cell cycle

PDB id: 1z2b

Contents

Protein chains

427 a.a. *

419 a.a. *

124 a.a. *

Ligands

GTP ×2

GDP ×2

CN2 ×2

VLB

Metals

_MG ×2

* Residue conservation analysis

PDB id:

1z2b

Name:

Cell cycle

Title:

Tubulin-colchicine-vinblastine: stathmin-like domain complex

Structure:

Tubulin alpha chain. Chain: a, c. Tubulin beta chain. Chain: b, d. Rb3 stathmin-like domain 4. Chain: e. Synonym: stathmin-like protein b3, rb3-sld. Engineered: yes

Source:

Bos taurus. Cattle. Organism_taxid: 9913. Organ: brain. Other_details: brain. Rattus norvegicus. Norway rat. Organism_taxid: 10116. Gene: stmn4.

Biol. unit:

Pentamer (from PQS)

Resolution:

4.10Å R-factor: 0.212 R-free: 0.269

Authors:

B.Gigant,C.Wang,R.B.G.Ravelli,F.Roussi,M.O.Steinmetz,P.A.Cur A.Sobel,M.Knossow

Key ref:

B.Gigant et al. (2005). Structural basis for the regulation of tubulin by vinblastine. Nature, 435, 519-522. PubMed id: 15917812 DOI: 10.1038/nature03566

Date:

08-Mar-05 Release date: 31-May-05

Protein chain

No UniProt id for this chain

Protein chains

Q6B856  (TBB2B_BOVIN) -  Tubulin beta-2B chain

Seq: 445 a.a.

Struc: 419 a.a.*

Protein chain

P63043  (STMN4_RAT) -  Stathmin-4

Seq: 189 a.a.

Struc: 124 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

 Gene Ontology (GO) functional annotation 

• Cellular component: protein complex (4 terms)
• Biological process: intracellular signal transduction (6 terms)
• Biochemical function: structural molecule activity (4 terms)

DOI no: 10.1038/nature03566

Nature 435:519-522 (2005)

PubMed id: 15917812

Structural basis for the regulation of tubulin by vinblastine.

B.Gigant, C.Wang, R.B.Ravelli, F.Roussi, M.O.Steinmetz, P.A.Curmi, A.Sobel, M.Knossow.

ABSTRACT

Vinblastine is one of several tubulin-targeting Vinca alkaloids that have been responsible for many chemotherapeutic successes since their introduction in the clinic as antitumour drugs. In contrast with the two other classes of small tubulin-binding molecules (Taxol and colchicine), the binding site of vinblastine is largely unknown and the molecular mechanism of this drug has remained elusive. Here we report the X-ray structure of vinblastine bound to tubulin in a complex with the RB3 protein stathmin-like domain (RB3-SLD). Vinblastine introduces a wedge at the interface of two tubulin molecules and thus interferes with tubulin assembly. Together with electron microscopical and biochemical data, the structure explains vinblastine-induced tubulin self-association into spiral aggregates at the expense of microtubule growth. It also shows that vinblastine and the amino-terminal part of RB3-SLD binding sites share a hydrophobic groove on the alpha-tubulin surface that is located at an intermolecular contact in microtubules. This is an attractive target for drugs designed to perturb microtubule dynamics by interfacial interference, for which tubulin seems ideally suited because of its propensity to self-associate.

Selected figure(s)

Figure 1.
Figure 1: The vinblastine-binding site. a, The location of vinblastine in (Tc)[2]R. (Tc)[2]R-bound vinblastine (Vlb, cyan) is shown as a space-filling model; the complex consists of RB3-SLD and two tubulin heterodimers, with colchicine (Col, yellow) bound to the -subunits at the interface with the -subunit. b, Left: chemical formula of vinblastine. Right: [a]-weighted F [obs] - F [calc] omit map of vinblastine-soaked (Tc)[2]R crystals contoured at 3.5 (magenta) overlapped with vinblastine; the difference electron density map between a C12'-bromovinblastine soaked (Tc)[2]R crystal after a low and a high dose of X-ray irradiation is shown in green (contoured at 5.5 ). c, Two perpendicular views of the vinblastine site. The labelled structural elements belong to the two domains that, together with a C-terminal helical hairpin, constitute the tubulin subunits. Loop T5 is part of the N-terminal 1 tubulin nucleotide-binding domain. Helix H6 and loop H6 -H7 link this domain to the intermediate domain. Helix H10, strand S9 and loop T7 are part of the 2 tubulin intermediate domain. Loops T5 and T7 contact the nucleotide in straight protofilaments.

Figure 3.
Figure 3: Kinetics of vinblastine binding to (Tc)[2]R.

The above figures are reprinted by permission from Macmillan Publishers Ltd: Nature (2005, 435, 519-522) copyright 2005.

Figures were selected by the author.