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Targeting Ligandable Pockets on Plant Homeodomain (PHD) Zinc Finger Domains by a Fragment-Based Approach.

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Amato A, Lucas X, Bortoluzzi A, Wright D, Ciulli A
OpenAccess logo ACS Chem Biol 13 915-921 (2018)
Related entries: 6fap, 6fhq, 6fhu, 6fi0, 6fi1

Cited: 16 times
EuropePMC logo PMID: 29529862

Abstract

Plant homeodomain (PHD) zinc fingers are histone reader domains that are often associated with human diseases. Despite this, they constitute a poorly targeted class of readers, suggesting low ligandability. Here, we describe a successful fragment-based campaign targeting PHD fingers from the proteins BAZ2A and BAZ2B as model systems. We validated a pool of in silico fragments both biophysically and structurally and solved the first crystal structures of PHD zinc fingers in complex with fragments bound to an anchoring pocket at the histone binding site. The best-validated hits were found to displace a histone H3 tail peptide in competition assays. This work identifies new chemical scaffolds that provide suitable starting points for future ligand optimization using structure-guided approaches. The demonstrated ligandability of the PHD reader domains could pave the way for the development of chemical probes to drug this family of epigenetic readers.

Articles - 6fkp mentioned but not cited (1)

  1. Targeting Ligandable Pockets on Plant Homeodomain (PHD) Zinc Finger Domains by a Fragment-Based Approach. Amato A, Lucas X, Bortoluzzi A, Wright D, Ciulli A. ACS Chem Biol 13 915-921 (2018)


Reviews citing this publication (4)

  1. Targeting epigenetic protein-protein interactions with small-molecule inhibitors. Linhares BM, Grembecka J, Cierpicki T. Future Med Chem 12 1305-1326 (2020)
  2. Atypical histone targets of PHD fingers. Black JC, Kutateladze TG. J Biol Chem 299 104601 (2023)
  3. Chemical tools targeting readers of lysine methylation. Ortiz G, Kutateladze TG, Fujimori DG. Curr Opin Chem Biol 74 102286 (2023)
  4. Non-histone binding functions of PHD fingers. Gaurav N, Kutateladze TG. Trends Biochem Sci 48 610-617 (2023)

Articles citing this publication (11)

  1. Identification and characterization of fragment binding sites for allosteric ligand design using the site identification by ligand competitive saturation hotspots approach (SILCS-Hotspots). MacKerell AD, Jo S, Lakkaraju SK, Lind C, Yu W. Biochim Biophys Acta Gen Subj 1864 129519 (2020)
  2. Surface Probing by Fragment-Based Screening and Computational Methods Identifies Ligandable Pockets on the von Hippel-Lindau (VHL) E3 Ubiquitin Ligase. Lucas X, Van Molle I, Ciulli A. J Med Chem 61 7387-7393 (2018)
  3. Covalent labeling of a chromatin reader domain using proximity-reactive cyclic peptides. Zhang MY, Yang H, Ortiz G, Trnka MJ, Petronikolou N, Burlingame AL, DeGrado WF, Fujimori DG. Chem Sci 13 6599-6609 (2022)
  4. Discovery and Mechanism of Small Molecule Inhibitors Selective for the Chromatin-Binding Domains of Oncogenic UHRF1. Liu WH, Miner RE, Albaugh BN, Ananiev GE, Wildman SA, Denu JM. Biochemistry 61 354-366 (2022)
  5. In silico derived small molecules targeting the finger-finger interaction between the histone lysine methyltransferase NSD1 and Nizp1 repressor. Berardi A, Ghitti M, Quilici G, Musco G. Comput Struct Biotechnol J 18 4082-4092 (2020)
  6. Extending the Detection Limit in Fragment Screening of Proteins Using Reverse Micelle Encapsulation. Fuglestad B, Kerstetter NE, Bédard S, Wand AJ. ACS Chem Biol 14 2224-2232 (2019)
  7. Identification of Histone Peptide Binding Specificity and Small-Molecule Ligands for the TRIM33α and TRIM33β Bromodomains. Sekirnik AR, Reynolds JK, See L, Bluck JP, Scorah AR, Tallant C, Lee B, Leszczynska KB, Grimley RL, Storer RI, Malattia M, Crespillo S, Caria S, Duclos S, Hammond EM, Knapp S, Morris GM, Duarte F, Biggin PC, Conway SJ. ACS Chem Biol 17 2753-2768 (2022)
  8. Crystal structure of the BAZ2B TAM domain. Feng Y, Chen S, Zhou M, Zhang J, Min J, Liu K. Heliyon 8 e09873 (2022)
  9. Dissecting the molecular basis for the modulation of neurotransmitter GPCR signaling by GINIP. Luebbers A, Gonzalez-Hernandez AJ, Zhou M, Eyles SJ, Levitz J, Garcia-Marcos M. Structure 32 47-59.e7 (2024)
  10. Fragment-Based NMR Screening of the BPTF PHD Finger Methyl Lysine Reader Leads to the First Small-Molecule Inhibitors. Buchholz CR, Sneddon MS, McPherson JE, Das S, Gee CT, Grillo MJ, Chai SC, Lee RE, Chen T, Harki DA, Shelat AA, Pomerantz WCK. ACS Med Chem Lett 14 1441-1447 (2023)
  11. Identifying ligands for the PHD1 finger of KDM5A through high-throughput screening. Ortiz G, Longbotham JE, Qin SL, Zhang MY, Lee GM, Neitz RJ, Kelly MJS, Arkin MR, Fujimori DG. RSC Chem Biol 5 209-215 (2024)


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