PDBsum entry 3lbl

Ligase

PDB id: 3lbl

Contents

Protein chains

94 a.a. *

85 a.a. *

Ligands

MI6 ×3

Waters ×296

* Residue conservation analysis

PDB id:

3lbl

Name:

Ligase

Title:

Structure of human mdm2 protein in complex with mi-63-analog

Structure:

E3 ubiquitin-protein ligase mdm2. Chain: a, c, e. Fragment: p53 binding domain. Synonym: p53-binding protein mdm2, oncoprotein mdm2, double minute 2 protein, hdm2. Engineered: yes

Source:

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

Resolution:

1.60Å R-factor: 0.193 R-free: 0.236

Authors:

G.M.Popowicz,A.Czarna,S.Wolf,T.A.Holak

Key ref:

G.M.Popowicz et al. (2010). Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery. Cell Cycle, 9, 1104-1111. PubMed id: 20237429 DOI: 10.4161/cc.9.6.10956

Date:

08-Jan-10 Release date: 16-Mar-10

Protein chains

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

Seq: 491 a.a.

Struc: 94 a.a.*

Protein chain

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

Seq: 491 a.a.

Struc: 85 a.a.

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

Enzyme reactions

• Enzyme class: Chains A, C, E: 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: 10.4161/cc.9.6.10956

Cell Cycle 9:1104-1111 (2010)

PubMed id: 20237429

Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery.

G.M.Popowicz, A.Czarna, S.Wolf, K.Wang, W.Wang, A.Dömling, T.A.Holak.

ABSTRACT

Intensive anticancer drug discovery efforts have been made to develop small molecule inhibitors of the p53-MDM2 and p53-MDMX interactions. We present here the structures of the most potent inhibitors bound to MDM2 and MDMX that are based on the new imidazo-indole scaffold. In addition, the structure of the recently reported spiro-oxindole inhibitor bound to MDM2 is described. The structures indicate how the substituents of a small molecule that bind to the three subpockets of the MDM2/X-p53 interaction should be optimized for effective binding to MDM2 and/or MDMX. While the spiro-oxindole inhibitor triggers significant ligand-induced changes in MDM2, the imidazo-indoles share similar binding modes for MDMX and MDM2, but cause only minimal induced-fit changes in the structures of both proteins. Our study includes the first structure of the complex between MDMX and a small molecule and should aid in developing efficient scaffolds for binding to MDMX and/or MDM2.