7CE6

Crystal structure of T2R-TTL-Compound9 complex

Summary for 7CE6

• Entry DOI: 10.2210/pdb7ce6/pdb
• Descriptor: Tubulin alpha-1B chain, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, N-benzyl-9H-beta-carbolin-3-amine, ... (13 entities in total)
• Functional Keywords: tubulin inhibitor, tublin, structural protein
• Biological source: Rattus norvegicus (Rat); More
• Total number of polymer chains: 6
• Total formula weight: 264834.30

Authors

Chen, L.J.,Chen, Q.,Yu, Y.,Yang, J.H. (deposition date: 2020-06-22, release date: 2021-06-30, Last modification date: 2023-11-29)

Primary citation

Yang, J.,Li, Y.,Qiu, Q.,Wang, R.,Yan, W.,Yu, Y.,Niu, L.,Pei, H.,Wei, H.,Ouyang, L.,Ye, H.,Xu, D.,Wei, Y.,Chen, Q.,Chen, L.
Small Molecules Promote Selective Denaturation and Degradation of Tubulin Heterodimers through a Low-Barrier Hydrogen Bond.
J.Med.Chem., 65:9159-9173, 2022

PubMed Abstract: Here, we report a novel mechanism to selectively degrade target proteins. 3-(3-Phenoxybenzyl)amino-β-carboline (PAC), a tubulin inhibitor, promotes selective degradation of αβ-tubulin heterodimers. Biochemical studies have revealed that PAC specifically denatures tubulin, making it prone to aggregation that predisposes it to ubiquitinylation and then degradation. The degradation is mediated by a single hydrogen bond formed between the pyridine nitrogen of PAC and βGlu198, which is identified as a low-barrier hydrogen bond (LBHB). In contrast, another two tubulin inhibitors that only form normal hydrogen bonds with βGlu198 exhibit no degradation effect. Thus, the LBHB accounts for the degradation. We then screened for compounds capable of forming an LBHB with βGlu198 and demonstrated that BML284, a Wnt signaling activator, also promotes tubulin heterodimer degradation through the LBHB. Our study provided a unique example of LBHB function and identified a novel approach to obtain tubulin degraders.

PubMed: 35762925
DOI: 10.1021/acs.jmedchem.2c00379

Experimental method

X-RAY DIFFRACTION (2.695 Å)