PDBsum entry 4zyc

Ligase

PDB id: 4zyc

Contents

Protein chains

84 a.a.

Ligands

4SS ×3

SO4

Waters ×104

PDB id:

4zyc

Name:

Ligase

Title:

Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-mdm2 interaction with a distinct binding mode: hdm2 (mdm2) complexed with cpd5

Structure:

E3 ubiquitin-protein ligase mdm2. Chain: a, b, c. Fragment: n-terminal domain, p53-binding domain, unp residues 17-111. Synonym: double minute 2 protein,hdm2,oncoprotein mdm2,p53-binding protein mdm2. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: mdm2. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.95Å R-factor: 0.222 R-free: 0.259

Authors:

J.Kallen

Key ref:

F.Gessier et al. (2015). Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode. Bioorg Med Chem Lett, 25, 3621-3625. PubMed id: 26141769 DOI: 10.1016/j.bmcl.2015.06.058

Date:

21-May-15 Release date: 22-Jul-15

Protein chains

Q00987  (MDM2_HUMAN) -  E3 ubiquitin-protein ligase Mdm2 from Homo sapiens

Seq: 491 a.a.

Struc: 84 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

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: 10.1016/j.bmcl.2015.06.058

Bioorg Med Chem Lett 25:3621-3625 (2015)

PubMed id: 26141769

Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode.

F.Gessier, J.Kallen, E.Jacoby, P.Chène, T.Stachyra-Valat, S.Ruetz, S.Jeay, P.Holzer, K.Masuya, P.Furet.

ABSTRACT

Blocking the interaction between the p53 tumor suppressor and its regulatory protein MDM2 is a promising therapeutic concept under current investigation in oncology drug research. We report here the discovery of the first representatives of a new class of small molecule inhibitors of this protein-protein interaction: the dihydroisoquinolinones. Starting from an initial hit identified by virtual screening, a derivatization program has resulted in compound 11, a low nanomolar inhibitor of the p53-MDM2 interaction showing significant cellular activity. Initially based on a binding mode hypothesis, this effort was then guided by a X-ray co-crystal structure of MDM2 in complex with one of the synthesized analogs. The X-ray structure revealed an unprecedented binding mode for p53-MDM2 inhibitors.