5XWR

Crystal Structure of RBBP4-peptide complex

Summary for 5XWR

• Entry DOI: 10.2210/pdb5xwr/pdb
• Descriptor: Histone-binding protein RBBP4, MET-SER-ARG-ARG-LYS-GLN-ALA-LYS-PRO-GLN-HIS-ILE (3 entities in total)
• Functional Keywords: histone binding protein, sall4, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 102919.60

Authors

Jobichen, C.,Lui, B.H.,Daniel, G.T.,Sivaraman, J. (deposition date: 2017-06-30, release date: 2018-07-11, Last modification date: 2023-11-22)

Primary citation

Liu, B.H.,Jobichen, C.,Chia, C.S.B.,Chan, T.H.M.,Tang, J.P.,Chung, T.X.Y.,Li, J.,Poulsen, A.,Hung, A.W.,Koh-Stenta, X.,Tan, Y.S.,Verma, C.S.,Tan, H.K.,Wu, C.S.,Li, F.,Hill, J.,Joy, J.,Yang, H.,Chai, L.,Sivaraman, J.,Tenen, D.G.
Targeting cancer addiction for SALL4 by shifting its transcriptome with a pharmacologic peptide.
Proc. Natl. Acad. Sci. U.S.A., 115:E7119-E7128, 2018

PubMed Abstract: Sal-like 4 (SALL4) is a nuclear factor central to the maintenance of stem cell pluripotency and is a key component in hepatocellular carcinoma, a malignancy with no effective treatment. In cancer cells, SALL4 associates with nucleosome remodeling deacetylase (NuRD) to silence tumor-suppressor genes, such as PTEN. Here, we determined the crystal structure of an amino-terminal peptide of SALL4(1-12) complexed to RBBp4, the chaperone subunit of NuRD, at 2.7 Å, and subsequent design of a potent therapeutic SALL4 peptide (FFW) capable of antagonizing the SALL4-NURD interaction using systematic truncation and amino acid substitution studies. FFW peptide disruption of the SALL4-NuRD complex resulted in unidirectional up-regulation of transcripts, turning SALL4 from a dual transcription repressor-activator mode to singular transcription activator mode. We demonstrate that FFW has a target affinity of 23 nM, and displays significant antitumor effects, inhibiting tumor growth by 85% in xenograft mouse models. Using transcriptome and survival analysis, we discovered that the peptide inhibits the transcription-repressor function of SALL4 and causes massive up-regulation of transcripts that are beneficial to patient survival. This study supports the SALL4-NuRD complex as a drug target and FFW as a viable drug candidate, showcasing an effective strategy to accurately target oncogenes previously considered undruggable.

PubMed: 29976840
DOI: 10.1073/pnas.1801253115

Experimental method

X-RAY DIFFRACTION (2.69 Å)