PDBsum entry 6b5q

Ligase/inhibitor

PDB id: 6b5q

Contents

Protein chains

190 a.a.

Ligands

PPI-CZS-2KY-MLY-1XY ×2

PGE ×2

Waters ×110

PDB id:

6b5q

Name:

Ligase/inhibitor

Title:

Dcn1 bound to 38

Structure:

Dcn1-like protein 1. Chain: a, b. Synonym: dcun1 domain-containing protein 1,defective in cullin neddylation protein 1-like protein 1,squamous cell carcinoma-related oncogene. Engineered: yes. Peptidomimetic inhibitors di-591. Chain: d, e. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: dcun1d1, dcun1l1, rp42, sccro. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic construct. Organism_taxid: 32630

Resolution:

2.16Å R-factor: 0.197 R-free: 0.241

Authors:

J.Stuckey

Key ref:

H.Zhou et al. (2018). High-Affinity Peptidomimetic Inhibitors of the DCN1-UBC12 Protein-Protein Interaction. J Med Chem, 61, 1934-1950. PubMed id: 29438612 DOI: 10.1021/acs.jmedchem.7b01455

Date:

29-Sep-17 Release date: 28-Feb-18

Protein chains

Q96GG9  (DCNL1_HUMAN) -  DCN1-like protein 1 from Homo sapiens

Seq: 259 a.a.

Struc: 190 a.a.

DOI no: 10.1021/acs.jmedchem.7b01455

J Med Chem 61:1934-1950 (2018)

PubMed id: 29438612

High-Affinity Peptidomimetic Inhibitors of the DCN1-UBC12 Protein-Protein Interaction.

H.Zhou, W.Zhou, B.Zhou, L.Liu, T.R.Chern, K.Chinnaswamy, J.Lu, D.Bernard, C.Y.Yang, S.Li, M.Wang, J.Stuckey, Y.Sun, S.Wang.

ABSTRACT

The Cullin-RING ligases (CRLs) regulate the turnover of approximately 20% of the proteins in mammalian cells and are emerging therapeutic targets in human diseases. The activation of CRLs requires the neddylation of their cullin subunit, which is controlled by an activation complex consisting of Cullin-RBX1-UBC12-NEDD8-DCN1. Herein, we describe the design, synthesis, and evaluation of peptidomimetics targeting the DCN1-UBC12 protein-protein interaction. Starting from a 12-residue UBC12 peptide, we have successfully obtained a series of peptidomimetic compounds that bind to DCN1 protein with K_Dvalues of <10 nM. Determination of a cocrystal structure of a potent peptidomimetic inhibitor complexed with DCN1 provides the structural basis for their high-affinity interaction. Cellular investigation of one potent DCN1 inhibitor, compound 36 (DI-404), reveals that it effectively and selectively inhibits the neddylation of cullin 3 over other cullin members. Further optimization of DI-404 may yield a new class of therapeutics for the treatment of human diseases in which cullin 3 CRL plays a key role.