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Crystal Structure of Tubulin-Stathmin-TTL-Tubulysin M ComplexCrystal Structure of Tubulin-Stathmin-TTL-Tubulysin M Complex
Structural highlights
Function[TBA1B_PIG] 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. [STMN4_RAT] Exhibits microtubule-destabilizing activity.[1] [2] [3] [TBB_PIG] 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. Publication Abstract from PubMedAntibody-drug conjugates (ADCs) have achieved great success in cancer therapy in recent years. Some peptidyl microtubule inhibitors consisting of natural and unnatural amino acids, such as monomethyl auristatin E (MMAE) and F (MMAF), are extremely cytotoxic and have been used as a payload in ADCs. However, their precise molecular interaction with tubulin and microtubules remains unclear. We determined the crystal structures of tubulin in complex with three ultra-potent peptidyl microtubule inhibitors [MMAE, taltobulin (HTI- 286), and tubulysin M] at 2.5 A. Our data showed that the three peptides bound to the vinca domain and shared a common and key pharmacophore containing two consecutive hydrophobic groups (Val, Ile-like side chain). These groups protruded in opposite directions into hydrophobic pockets on the tubulin beta and alpha subunits. Nitrogen and oxygen atoms from the same backbone formed hydrogen bonds with Asn329 from the alpha subunit and Asp179 from the beta subunit in a direction normal to the surface formed by the aforementioned hydrophobic groups. In addition, our crystal structure data indicated that tubulysin M bound to the beta subunit alone, providing a structural explanation for its higher affinity. We also compared the conformations of two representative structurally different vinca domain compounds, ustiloxin D and vinblastine, with those of the aforementioned peptidyl ligands, and found that they shared a similar pharmacophore. Our findings lay a foundation for the rational design of novel vinca domain ligands and may facilitate the development of microtubule inhibitors with high specificity, affinity, and efficiency as payloads for ADCs in cancer therapy. Structural Insights into the Pharmacophore of Vinca Domain Inhibitors of Microtubules.,Wang Y, Benz FW, Wu Y, Wang Q, Chen Y, Chen X, Li H, Zhang Y, Zhang R, Yang J Mol Pharmacol. 2016 Feb;89(2):233-42. doi: 10.1124/mol.115.100149. Epub 2015 Dec , 9. PMID:26660762[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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