PDBsum entry 6xmx

Transcription

PDB id: 6xmx

Contents

Protein chains

(+ 2 more) 122 a.a.

Ligands

U52 ×8

PDB id:

6xmx

Name:

Transcription

Title:

Cryo-em structure of bcl6 bound to bi-3802

Structure:

B-cell lymphoma 6 protein. Chain: a, b, c, d, e, f, g, h. Synonym: bcl-6,b-cell lymphoma 5 protein,bcl-5,protein laz-3,zinc finger and btb domain-containing protein 27,zinc finger protein 51. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: bcl6, bcl5, laz3, zbtb27, znf51. Expressed in: trichoplusia ni. Expression_system_taxid: 7111.

Authors:

H.Yoon,S.S.R.Burman,M.Hunkeler,R.P.Nowak,E.S.Fischer

Key ref:

M.Słabicki et al. (2020). Small-molecule-induced polymerization triggers degradation of BCL6. Nature, 588, 164-168. PubMed id: 33208943 DOI: 10.1038/s41586-020-2925-1

Date:

01-Jul-20 Release date: 25-Nov-20

Protein chains

P41182  (BCL6_HUMAN) -  B-cell lymphoma 6 protein from Homo sapiens

Seq: 706 a.a.

Struc: 122 a.a.

Enzyme reactions

• Enzyme class: E.C.?

DOI no: 10.1038/s41586-020-2925-1

Nature 588:164-168 (2020)

PubMed id: 33208943

Small-molecule-induced polymerization triggers degradation of BCL6.

M.Słabicki, H.Yoon, J.Koeppel, L.Nitsch, S.S.Roy Burman, C.Di Genua, K.A.Donovan, A.S.Sperling, M.Hunkeler, J.M.Tsai, R.Sharma, A.Guirguis, C.Zou, P.Chudasama, J.A.Gasser, P.G.Miller, C.Scholl, S.Fröhling, R.P.Nowak, E.S.Fischer, B.L.Ebert.

ABSTRACT

Effective and sustained inhibition of non-enzymatic oncogenic driver proteins is a major pharmacological challenge. The clinical success of thalidomide analogues demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets^1-3, but a substantial subset of proteins are resistant to targeted degradation using existing approaches^4,5. Here we report an alternative mechanism of targeted protein degradation, in which a small molecule induces the highly specific, reversible polymerization of a target protein, followed by its sequestration into cellular foci and subsequent degradation. BI-3802 is a small molecule that binds to the Broad-complex, Tramtrack and Bric-à-brac (BTB) domain of the oncogenic transcription factor B cell lymphoma 6 (BCL6) and leads to the proteasomal degradation of BCL6⁶. We use cryo-electron microscopy to reveal how the solvent-exposed moiety of a BCL6-binding molecule contributes to a composite ligand-protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology.