7cbz

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Crystal structure of T2R-TTL-A31 complex

Structural highlights

7cbz is a 6 chain structure with sequence from Gallus gallus, Rattus norvegicus and Sus scrofa. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.61Å
Ligands:CA, FUO, GDP, GTP, MES, MG
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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.

Publication Abstract from PubMed

Klisyri (KX01) is a dual tubulin/Src protein inhibitor that has shown potential therapeutic effects in several tumor models. However, a phase II clinical trial in patients with bone-metastatic castration-resistant prostate cancer was halted because of lack of efficacy. We previously reported that KX01 binds to the colchicine site of beta-tubulin and its morpholine group lies close to alpha-tubulin's surface. Thus, we hypothesized that enhancing the interaction of KX01 with alpha-tubulin could increase tubulin inhibition and synthesized a series of KX01 derivatives directed by docking studies. Among these derivatives, 8a exhibited more than 10-fold antiproliferation activity in several tumor cells than KX01 and significantly improved in vivo antitumor effects. The X-ray crystal structure suggested that 8a both bound to the colchicine site and extended into the interior of alpha-tubulin to form potent interactions, presenting a novel binding mode. A potential clinical candidate for cancer therapy was identified in this study.

Design, Synthesis, and Bioactivity Evaluation of Dual-Target Inhibitors of Tubulin and Src Kinase Guided by Crystal Structure.,Wang L, Zheng Y, Li D, Yang J, Lei L, Yan W, Zheng W, Tang M, Shi M, Zhang R, Cai X, Ni H, Ma X, Li N, Hong F, Ye H, Chen L J Med Chem. 2021 Jun 24;64(12):8127-8141. doi: 10.1021/acs.jmedchem.0c01961. Epub , 2021 Jun 3. PMID:34081857[1]

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

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Citations
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Molecular Docking, Molecular Dynamics Simulations, and Free Energy Calculation Insights into the Binding Mechanism between VS-4718 and Focal Adhesion Kinase.
Shi et al. (2022)
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See Also

References

  1. ↑ Wang L, Zheng Y, Li D, Yang J, Lei L, Yan W, Zheng W, Tang M, Shi M, Zhang R, Cai X, Ni H, Ma X, Li N, Hong F, Ye H, Chen L. Design, Synthesis, and Bioactivity Evaluation of Dual-Target Inhibitors of Tubulin and Src Kinase Guided by Crystal Structure. J Med Chem. 2021 Jun 24;64(12):8127-8141. PMID:34081857 doi:10.1021/acs.jmedchem.0c01961

Contents


PDB ID 7cbz

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OCA

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