5JSJ

Crystal structure of Spindlin1 bound to compound EML631

Summary for 5JSJ

• Entry DOI: 10.2210/pdb5jsj/pdb
• Related: 5JSG
• Descriptor: Spindlin-1, [4-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]-[4-[4-(2-pyrrolidin-1-ylethyl)piperidin-1-yl]carbonyl-3-[[4-(pyrrolidin-1-ylmethoxy)phenyl]amino]phenyl]methanone, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: tudor domain, cell cycle
• Biological source: Homo sapiens (Human)
• Cellular location: Nucleus : Q9Y657
• Total number of polymer chains: 2
• Total formula weight: 52484.61

Authors

Su, X.,Li, H. (deposition date: 2016-05-08, release date: 2017-05-24, Last modification date: 2024-03-20)

Primary citation

Bae, N.,Viviano, M.,Su, X.,Lv, J.,Cheng, D.,Sagum, C.,Castellano, S.,Bai, X.,Johnson, C.,Khalil, M.I.,Shen, J.,Chen, K.,Li, H.,Sbardella, G.,Bedford, M.T.
Developing Spindlin1 small-molecule inhibitors by using protein microarrays
Nat. Chem. Biol., 13:750-756, 2017

PubMed Abstract: The discovery of inhibitors of methyl- and acetyl-binding domains has provided evidence for the 'druggability' of epigenetic effector molecules. The small-molecule probe UNC1215 prevents methyl-dependent protein-protein interactions by engaging the aromatic cage of MBT domains and, with lower affinity, Tudor domains. Using a library of tagged UNC1215 analogs, we screened a protein-domain microarray of human methyllysine effector molecules to rapidly detect compounds with new binding profiles with either increased or decreased specificity. Using this approach, we identified a compound (EML405) that acquired a novel interaction with the Tudor-domain-containing protein Spindlin1 (SPIN1). Structural studies facilitated the rational synthesis of SPIN1 inhibitors with increased selectivity (EML631-633), which engage SPIN1 in cells, block its ability to 'read' H3K4me3 marks and inhibit its transcriptional-coactivator activity. Protein microarrays can thus be used as a platform to 'target-hop' and identify small molecules that bind and compete with domain-motif interactions.

PubMed: 28504676
DOI: 10.1038/nchembio.2377

Experimental method

X-RAY DIFFRACTION (2.348 Å)