PDBsum entry 4j3e

Ligase/antagonist

PDB id: 4j3e

Contents

Protein chain

86 a.a.

Ligands

NUT

SO4

Waters ×128

PDB id:

4j3e

Name:

Ligase/antagonist

Title:

The 1.9a crystal structure of humanized xenopus mdm2 with nutlin-3a

Structure:

E3 ubiquitin-protein ligase mdm2. Chain: a. Fragment: n-terminal domain (unp residues 21-105). Synonym: double minute 2 protein, xdm2, p53-binding protein mdm2. Engineered: yes. Mutation: yes

Source:

Xenopus laevis. Clawed frog,common platanna,platanna. Organism_taxid: 8355. Gene: mdm2. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

1.91Å R-factor: 0.196 R-free: 0.239

Authors:

B.J.Graves,C.M.Lukacs,R.U.Kammlott,R.Crowther

Key ref:

B.Vu et al. (2013). Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development. Acs Med Chem Lett, 4, 466-469. PubMed id: 24900694 DOI: 10.1021/ml4000657

Date:

05-Feb-13 Release date: 24-Apr-13

Protein chain

P56273  (MDM2_XENLA) -  E3 ubiquitin-protein ligase Mdm2 from Xenopus laevis

Seq: 473 a.a.

Struc: 86 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.2.3.2.27 - RING-type E3 ubiquitin transferase.
• Reaction: S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine + [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-cysteine + N₆- ubiquitinyl-[acceptor protein]-L-lysine

DOI no: 10.1021/ml4000657

Acs Med Chem Lett 4:466-469 (2013)

PubMed id: 24900694

Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development.

B.Vu, P.Wovkulich, G.Pizzolato, A.Lovey, Q.Ding, N.Jiang, J.J.Liu, C.Zhao, K.Glenn, Y.Wen, C.Tovar, K.Packman, L.Vassilev, B.Graves.

ABSTRACT

The p53 tumor suppressor is a potent transcription factor that plays a key role in the regulation of cellular responses to stress. It is controlled by its negative regulator MDM2, which binds directly to p53 and inhibits its transcriptional activity. MDM2 also targets p53 for degradation by the proteasome. Many tumors produce high levels of MDM2, thereby impairing p53 function. Restoration of p53 activity by inhibiting the p53-MDM2 interaction may represent a novel approach to cancer treatment. RG7112 (2g) is the first clinical small-molecule MDM2 inhibitor designed to occupy the p53-binding pocket of MDM2. In cancer cells expressing wild-type p53, RG7112 stabilizes p53 and activates the p53 pathway, leading to cell cycle arrest, apoptosis, and inhibition or regression of human tumor xenografts.