PDBsum entry 4w9c

Ligase

PDB id: 4w9c

Contents

Protein chains

103 a.a.

86 a.a.

141 a.a.

88 a.a.

88 a.a.

Ligands

3JG ×4

Waters ×526

PDB id:

4w9c

Name:

Ligase

Title:

Pvhl:elob:eloc in complex with (2s,4r)-1-(3,3-dimethylbutanoyl)-4- hydroxy-n-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide (ligand 2)

Structure:

Transcription elongation factor b polypeptide 2. Chain: a, d, g, j. Synonym: elongin 18 kda subunit,elongin-b,elob,RNA polymerase ii transcription factor siii subunit b,siii p18. Engineered: yes. Transcription elongation factor b polypeptide 1. Chain: b, e, h, k. Synonym: elongin 15 kda subunit,elongin-c,eloc,RNA polymerase ii transcription factor siii subunit c,siii p15.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tceb2. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Gene: tceb1. Gene: vhl.

Resolution:

2.20Å R-factor: 0.209 R-free: 0.251

Authors:

M.S.Gadd,S.Hewitt,C.Galdeano,I.Van Molle,A.Ciulli

Key ref:

C.Galdeano et al. (2014). Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities. J Med Chem, 57, 8657-8663. PubMed id: 25166285 DOI: 10.1021/jm5011258

Date:

27-Aug-14 Release date: 10-Sep-14

Protein chains

Q15370  (ELOB_HUMAN) -  Elongin-B from Homo sapiens

Seq: 118 a.a.

Struc: 103 a.a.*

Protein chain

Q15369  (ELOC_HUMAN) -  Elongin-C from Homo sapiens

Seq: 112 a.a.

Struc: 86 a.a.

Protein chains

P40337  (VHL_HUMAN) -  von Hippel-Lindau disease tumor suppressor from Homo sapiens

Seq: 213 a.a.

Struc: 141 a.a.*

Protein chains

Q15369  (ELOC_HUMAN) -  Elongin-C from Homo sapiens

Seq: 112 a.a.

Struc: 88 a.a.

Protein chain

Q15369  (ELOC_HUMAN) -  Elongin-C from Homo sapiens

Seq: 112 a.a.

Struc: 88 a.a.*

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

DOI no: 10.1021/jm5011258

J Med Chem 57:8657-8663 (2014)

PubMed id: 25166285

Structure-guided design and optimization of small molecules targeting the protein-protein interaction between the von Hippel-Lindau (VHL) E3 ubiquitin ligase and the hypoxia inducible factor (HIF) alpha subunit with in vitro nanomolar affinities.

C.Galdeano, M.S.Gadd, P.Soares, S.Scaffidi, I.Van Molle, I.Birced, S.Hewitt, D.M.Dias, A.Ciulli.

ABSTRACT

E3 ubiquitin ligases are attractive targets in the ubiquitin-proteasome system, however, the development of small-molecule ligands has been rewarded with limited success. The von Hippel-Lindau protein (pVHL) is the substrate recognition subunit of the VHL E3 ligase that targets HIF-1α for degradation. We recently reported inhibitors of the pVHL:HIF-1α interaction, however they exhibited moderate potency. Herein, we report the design and optimization, guided by X-ray crystal structures, of a ligand series with nanomolar binding affinities.