PDBsum entry 4ajy

Transcription

PDB id: 4ajy

Contents

Protein chains

105 a.a.

88 a.a.

15 a.a.

148 a.a.

Ligands

GOL

Waters ×242

PDB id:

4ajy

Name:

Transcription

Title:

Von hippel-lindau protein-elonginb-elonginc complex, bound to hif1- alpha peptide

Structure:

Transcription elongation factor b polypeptide 2. Chain: b. 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: c. Fragment: 17-112. Synonym: elongin 15 kda subunit, elongin-c, eloc, RNA polymerase ii

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Synthetic: yes. Human source 19.

Resolution:

1.73Å R-factor: 0.192 R-free: 0.232

Authors:

I.Van Molle,A.Thomann,D.L.Buckley,E.C.So,S.Lang,C.M.Crews,A.Ciulli

Key ref:

I.Van Molle et al. (2012). Dissecting fragment-based lead discovery at the von Hippel-Lindau protein:hypoxia inducible factor 1α protein-protein interface. Chem Biol, 19, 1300-1312. PubMed id: 23102223

Date:

21-Feb-12 Release date: 14-Nov-12

Protein chain

Q15370  (ELOB_HUMAN) -  Elongin-B from Homo sapiens

Seq: 118 a.a.

Struc: 105 a.a.

Protein chain

Q15369  (ELOC_HUMAN) -  Elongin-C from Homo sapiens

Seq: 112 a.a.

Struc: 88 a.a.

Protein chain

Q16665  (HIF1A_HUMAN) -  Hypoxia-inducible factor 1-alpha from Homo sapiens

Seq: 826 a.a.

Struc: 15 a.a.*

Protein chain

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

Seq: 213 a.a.

Struc: 148 a.a.

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Chem Biol 19:1300-1312 (2012)

PubMed id: 23102223

Dissecting fragment-based lead discovery at the von Hippel-Lindau protein:hypoxia inducible factor 1α protein-protein interface.

I.Van Molle, A.Thomann, D.L.Buckley, E.C.So, S.Lang, C.M.Crews, A.Ciulli.

ABSTRACT

Fragment screening is widely used to identify attractive starting points for drug design. However, its potential and limitations to assess the tractability of often challenging protein:protein interfaces have been underexplored. Here, we address this question by means of a systematic deconstruction of lead-like inhibitors of the pVHL:HIF-1α interaction into their component fragments. Using biophysical techniques commonly employed for screening, we could only detect binding of fragments that violate the Rule of Three, are more complex than those typically screened against classical druggable targets, and occupy two adjacent binding subsites at the interface rather than just one. Analyses based on ligand and group lipophilicity efficiency of anchored fragments were applied to dissect the individual subsites and probe for binding hot spots. The implications of our findings for targeting protein interfaces by fragment-based approaches are discussed.