PDBsum entry 4ap2

Cell cycle

PDB id: 4ap2

Contents

Protein chains

266 a.a.

359 a.a.

Ligands

EDO ×4

Metals

IOD

_CL

Waters ×207

PDB id:

4ap2

Name:

Cell cycle

Title:

Crystal structure of the human klhl11-cul3 complex at 2.8a resolution

Structure:

Kelch-like protein 11. Chain: a. Fragment: btb and back domain, residues 67-340. Engineered: yes. Cullin-3. Chain: b. Fragment: n-terminal domain, residues 1-388. Synonym: cul-3. Engineered: yes.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: r3 prare2. Expression_system_variant: r3.

Resolution:

2.80Å R-factor: 0.206 R-free: 0.236

Authors:

P.Canning,C.D.O.Cooper,T.Krojer,P.Filippakopoulos,V.Ayinampudi, C.H.Arrowsmith,A.M.Edwards,C.Bountra,F.Von Delft,A.N.Bullock, Structural Genomics Consortium (Sgc)

Key ref:

P.Canning et al. (2013). Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases. J Biol Chem, 288, 7803-7814. PubMed id: 23349464 DOI: 10.1074/jbc.M112.437996

Date:

30-Mar-12 Release date: 09-May-12

Protein chain

Q9NVR0  (KLH11_HUMAN) -  Kelch-like protein 11 from Homo sapiens

Seq: 708 a.a.

Struc: 266 a.a.

Protein chain

Q13618  (CUL3_HUMAN) -  Cullin-3 from Homo sapiens

Seq: 768 a.a.

Struc: 359 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

DOI no: 10.1074/jbc.M112.437996

J Biol Chem 288:7803-7814 (2013)

PubMed id: 23349464

Structural basis for Cul3 protein assembly with the BTB-Kelch family of E3 ubiquitin ligases.

P.Canning, C.D.Cooper, T.Krojer, J.W.Murray, A.C.Pike, A.Chaikuad, T.Keates, C.Thangaratnarajah, V.Hojzan, V.Ayinampudi, B.D.Marsden, O.Gileadi, S.Knapp, F.von Delft, A.N.Bullock.

ABSTRACT

Cullin-RING ligases are multisubunit E3 ubiquitin ligases that recruit substrate-specific adaptors to catalyze protein ubiquitylation. Cul3-based Cullin-RING ligases are uniquely associated with BTB adaptors that incorporate homodimerization, Cul3 assembly, and substrate recognition into a single multidomain protein, of which the best known are BTB-BACK-Kelch domain proteins, including KEAP1. Cul3 assembly requires a BTB protein "3-box" motif, analogous to the F-box and SOCS box motifs of other Cullin-based E3s. To define the molecular basis for this assembly and the overall architecture of the E3, we determined the crystal structures of the BTB-BACK domains of KLHL11 both alone and in complex with Cul3, along with the Kelch domain structures of KLHL2 (Mayven), KLHL7, KLHL12, and KBTBD5. We show that Cul3 interaction is dependent on a unique N-terminal extension sequence that packs against the 3-box in a hydrophobic groove centrally located between the BTB and BACK domains. Deletion of this N-terminal region results in a 30-fold loss in affinity. The presented data offer a model for the quaternary assembly of this E3 class that supports the bivalent capture of Nrf2 and reveals potential new sites for E3 inhibitor design.