PDBsum entry 6hax

Gene regulation

PDB id: 6hax

Contents

Protein chains

115 a.a.

149 a.a.

88 a.a.

104 a.a.

121 a.a.

97 a.a.

Ligands

EDO ×14

FWZ ×2

EPE

Waters ×213

PDB id:

6hax

Name:

Gene regulation

Title:

Crystal structure of protac 2 in complex with the bromodomain of human smarca2 and pvhl:elonginc:elonginb

Structure:

Probable global transcription activator snf2l2. Chain: a, e. Synonym: atp-dependent helicase smarca2,brg1-associated factor 190b, baf190b,protein brahma homolog,hbrm,snf2-alpha,swi/snf-related matrix-associated actin-dependent regulator of chromatin subfamily a member 2. Engineered: yes. Von hippel-lindau disease tumor suppressor. Chain: b, f.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: smarca2, baf190b, brm, snf2a, snf2l2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: vhl. Gene: eloc, tceb1. Gene: elob, tceb2.

Resolution:

2.35Å R-factor: 0.234 R-free: 0.268

Authors:

M.Roy,G.Bader,E.Diers,N.Trainor,W.Farnaby,A.Ciulli

Key ref:

W.Farnaby et al. (2019). BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design. Nat Chem Biol, 15, 672-680. PubMed id: 31178587

Date:

09-Aug-18 Release date: 12-Jun-19

Protein chain

P51531  (SMCA2_HUMAN) -  Probable global transcription activator SNF2L2 from Homo sapiens

Seq: 1590 a.a.

Struc: 115 a.a.

Protein chains

P40337  (VHL_HUMAN) -  von Hippel-Lindau disease tumor suppressor from Homo sapiens

Seq: 213 a.a.

Struc: 149 a.a.

Protein chain

Q15369  (ELOC_HUMAN) -  Elongin-C from Homo sapiens

Seq: 112 a.a.

Struc: 88 a.a.*

Protein chains

Q15370  (ELOB_HUMAN) -  Elongin-B from Homo sapiens

Seq: 118 a.a.

Struc: 104 a.a.

Protein chain

P51531  (SMCA2_HUMAN) -  Probable global transcription activator SNF2L2 from Homo sapiens

Seq: 1590 a.a.

Struc: 121 a.a.*

Protein chain

Q15369  (ELOC_HUMAN) -  Elongin-C from Homo sapiens

Seq: 112 a.a.

Struc: 97 a.a.*

* PDB and UniProt seqs differ at 3 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chains A, E: E.C.3.6.4.- - ?????
• Enzyme class 3: Chains B, C, D, F, G, H: E.C.?

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Nat Chem Biol 15:672-680 (2019)

PubMed id: 31178587

BAF complex vulnerabilities in cancer demonstrated via structure-based PROTAC design.

W.Farnaby, M.Koegl, M.J.Roy, C.Whitworth, E.Diers, N.Trainor, D.Zollman, S.Steurer, J.Karolyi-Oezguer, C.Riedmueller, T.Gmaschitz, J.Wachter, C.Dank, M.Galant, B.Sharps, K.Rumpel, E.Traxler, T.Gerstberger, R.Schnitzer, O.Petermann, P.Greb, H.Weinstabl, G.Bader, A.Zoephel, A.Weiss-Puxbaum, K.Ehrenhöfer-Wölfer, S.Wöhrle, G.Boehmelt, J.Rinnenthal, H.Arnhof, N.Wiechens, M.Y.Wu, T.Owen-Hughes, P.Ettmayer, M.Pearson, D.B.McConnell, A.Ciulli.

ABSTRACT

Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases.