4AJY

von Hippel-Lindau protein-ElonginB-ElonginC complex, bound to Hif1- alpha peptide

Summary for 4AJY

• Entry DOI: 10.2210/pdb4ajy/pdb
• Related: 1D7G 1H2K 1H2L 1H2M 1L3E 1L8C 1LM8 1LQB 1VCB 2C9W 2IZV 2XAI 3ZRC 3ZRF 3ZTC 3ZTD 3ZUN
• Descriptor: TRANSCRIPTION ELONGATION FACTOR B POLYPEPTIDE 2, TRANSCRIPTION ELONGATION FACTOR B POLYPEPTIDE 1, HYPOXIA-INDUCIBLE FACTOR 1-ALPHA, ... (6 entities in total)
• Functional Keywords: e3 ubiquitin ligase, transcription factor, hypoxic signaling, transcription
• Biological source: HOMO SAPIENS (HUMAN); More
• Cellular location: Nucleus (Probable): Q15370 Q15369; Cytoplasm: Q16665; Isoform 1: Cytoplasm. Isoform 3: Cytoplasm: P40337
• Total number of polymer chains: 4
• Total formula weight: 45315.39

Authors

Van Molle, I.,Thomann, A.,Buckley, D.L.,So, E.C.,Lang, S.,Crews, C.M.,Ciulli, A. (deposition date: 2012-02-21, release date: 2012-11-14, Last modification date: 2023-12-20)

Primary citation

Van Molle, I.,Thomann, A.,Buckley, D.L.,So, E.C.,Lang, S.,Crews, C.M.,Ciulli, A.
Dissecting Fragment-Based Lead Discovery at the Von Hippel-Lindau Protein:Hypoxia Inducible Factor 1Alpha Protein-Protein Interface.
Chem.Biol., 19:1300-, 2012

PubMed 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.

PubMed: 23102223
DOI: 10.1016/J.CHEMBIOL.2012.08.015

Experimental method

X-RAY DIFFRACTION (1.73 Å)