PDBsum entry 4ci2

DNA binding protein/protein binding

PDB id: 4ci2

Contents

Protein chains

1091 a.a.

370 a.a.

Ligands

LVY

Metals

_ZN

Waters ×8

PDB id:

4ci2

Name:

DNA binding protein/protein binding

Title:

Structure of the ddb1-crbn e3 ubiquitin ligase bound to lenalidomide

Structure:

DNA damage-binding protein 1. Chain: a. Synonym: ddb p127 subunit, DNA damage-binding protein a, ddba, damage-specific DNA-binding protein 1, hbv x-associated protein 1, xap-1, uv-damaged DNA-binding factor, uv-damaged DNA-binding protein 1, uv-ddb 1, xpe-binding factor, xpe-bf, xeroderma pigmentosum group e-complementing protein, xpce. Engineered: yes. Protein cereblon.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Expression_system_cell_line: high five. Gallus gallus. Chicken. Organism_taxid: 9031.

Resolution:

2.95Å R-factor: 0.195 R-free: 0.234

Authors:

E.S.Fischer,K.Boehm,N.H.Thoma

Key ref:

E.S.Fischer et al. (2014). Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature, 512, 49-53. PubMed id: 25043012 DOI: 10.1038/nature13527

Date:

05-Dec-13 Release date: 16-Jul-14

Protein chain

Q16531  (DDB1_HUMAN) -  DNA damage-binding protein 1 from Homo sapiens

Seq: 1140 a.a.

Struc: 1091 a.a.

Protein chain

P0CF65  (CRBN_CHICK) -  Protein cereblon from Gallus gallus

Seq: 445 a.a.

Struc: 370 a.a.

Enzyme reactions

• Enzyme class: Chains A, B: E.C.?

DOI no: 10.1038/nature13527

Nature 512:49-53 (2014)

PubMed id: 25043012

Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide.

E.S.Fischer, K.Böhm, J.R.Lydeard, H.Yang, M.B.Stadler, S.Cavadini, J.Nagel, F.Serluca, V.Acker, G.M.Lingaraju, R.B.Tichkule, M.Schebesta, W.C.Forrester, M.Schirle, U.Hassiepen, J.Ottl, M.Hild, R.E.Beckwith, J.W.Harper, J.L.Jenkins, N.H.Thomä.

ABSTRACT

In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins.