7m20

From Proteopedia

18-mer HeLa-tubulin rings in complex with Cryptophycin 1

Structural highlights

7m20 is a 18 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.84Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TBB3_HUMAN Congenital fibrosis of extraocular muscles;Cortical dysgenesis with pontocerebellar hypoplasia due to TUBB3 mutation. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

TBB3_HUMAN Tubulin is the major constituent of microtubules. It binds two moles of GTP, one at an exchangeable site on the beta chain and one at a non-exchangeable site on the alpha chain. TUBB3 plays a critical role in proper axon guidance and mantainance.^[1]

Publication Abstract from PubMed

Cryptophycin-52 (Cp-52) is potentially the most potent anticancer drug known, with IC(50) values in the low picomolar range, but its binding site on tubulin and mechanism of action are unknown. Here, we have determined the binding site of Cp-52, and its parent compound, cryptophycin-1, on HeLa tubulin, to a resolution of 3.3 A and 3.4 A, respectively, by cryo-EM and characterized this binding further by molecular dynamics simulations. The binding site was determined to be located at the tubulin interdimer interface and partially overlap that of maytansine, another cytotoxic tubulin inhibitor. Binding induces curvature both within and between tubulin dimers that is incompatible with the microtubule lattice. Conformational changes occur in both alpha-tubulin and beta-tubulin, particularly in helices H8 and H10, with distinct differences between alpha and beta monomers and between Cp-52-bound and cryptophycin-1-bound tubulin. From these results, we have determined: (i) the mechanism of action of inhibition of both microtubule polymerization and depolymerization, (ii) how the affinity of Cp-52 for tubulin may be enhanced, and (iii) where linkers for targeted delivery can be optimally attached to this molecule.

Conformational changes in tubulin upon binding cryptophycin-52 reveal its mechanism of action.,Eren E, Watts NR, Sackett DL, Wingfield PT J Biol Chem. 2021 Oct;297(4):101138. doi: 10.1016/j.jbc.2021.101138. Epub 2021 , Aug 28. PMID:34461087^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tischfield MA, Baris HN, Wu C, Rudolph G, Van Maldergem L, He W, Chan WM, Andrews C, Demer JL, Robertson RL, Mackey DA, Ruddle JB, Bird TD, Gottlob I, Pieh C, Traboulsi EI, Pomeroy SL, Hunter DG, Soul JS, Newlin A, Sabol LJ, Doherty EJ, de Uzcategui CE, de Uzcategui N, Collins ML, Sener EC, Wabbels B, Hellebrand H, Meitinger T, de Berardinis T, Magli A, Schiavi C, Pastore-Trossello M, Koc F, Wong AM, Levin AV, Geraghty MT, Descartes M, Flaherty M, Jamieson RV, Moller HU, Meuthen I, Callen DF, Kerwin J, Lindsay S, Meindl A, Gupta ML Jr, Pellman D, Engle EC. Human TUBB3 mutations perturb microtubule dynamics, kinesin interactions, and axon guidance. Cell. 2010 Jan 8;140(1):74-87. doi: 10.1016/j.cell.2009.12.011. PMID:20074521 doi:http://dx.doi.org/10.1016/j.cell.2009.12.011
↑ Eren E, Watts NR, Sackett DL, Wingfield PT. Conformational changes in tubulin upon binding cryptophycin-52 reveal its mechanism of action. J Biol Chem. 2021 Oct;297(4):101138. PMID:34461087 doi:10.1016/j.jbc.2021.101138