5H7H

Crystal structure of the BCL6 BTB domain in complex with F1324(10-13)

Summary for 5H7H

• Entry DOI: 10.2210/pdb5h7h/pdb
• Related: 5H7G
• Descriptor: B-cell lymphoma 6 protein, F1324 peptide residues 10-13, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: transcription repressor, complex, inhibitor, transcription-inhibitor complex, transcription/inhibitor
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 3
• Total formula weight: 17517.20

Authors

Sogabe, S.,Ida, K.,Lane, W.,Snell, G. (deposition date: 2016-11-18, release date: 2016-12-07, Last modification date: 2024-10-16)

Primary citation

Sakamoto, K.,Sogabe, S.,Kamada, Y.,Sakai, N.,Asano, K.,Yoshimatsu, M.,Ida, K.,Imaeda, Y.,Sakamoto, J.I.
Discovery of high-affinity BCL6-binding peptide and its structure-activity relationship.
Biochem. Biophys. Res. Commun., 482:310-316, 2017

PubMed Abstract: B cell lymphoma 6 (BCL6) is a transcriptional repressor that interacts with its corepressors BcoR and SMRT. Since this protein-protein interaction (PPI) induces activation and differentiation of B lymphocytes, BCL6 has been an attractive drug target for potential autoimmune disease treatments. Here we report a novel BCL6 inhibitory peptide, F1324 (Ac-LWYTDIRMSWRVP-OH), which we discovered using phage display technology; we also discuss this peptide's structure-activity relationship (SAR). For BCL6(5-129) binding, K and IC values of F1324 were 0.57 nM and 1 nM according to the results of an SPR analysis and cell-free ELISA assay, respectively. In contrast, BcoR(Arg498-514Pro) and SMRT(Leu1422-Arg1438) exhibited relatively weak micromole-order binding to BCL6. Furthermore, Fusion protein AcGFP-F1324 transiently expressed in HEK293T cells inhibited intracellular PPI in cell-based M2H assay. By examination of the truncation and fragmentation of F1324, the C-terminal sequence WRVP, which is similar to the BcoR(509-512) sequence WVVP, was identified as being critical for BCL6 binding. In addition, subsequent single-crystal X-ray diffraction analysis of F1324/BCL6(5-129) complex revealed that the high affinity of F1324 was caused by effective interaction of its side chains while its main chain structure was similar to that of BcoR(Arg498-514Pro). To our knowledge, F1324 is the strongest BCL6-binding peptide yet reported.

PubMed: 27856253
DOI: 10.1016/j.bbrc.2016.11.060

Experimental method

X-RAY DIFFRACTION (1.95 Å)