6CZ5
Crystal structure of small molecule AMP-acrylamide covalently bound to DDX3 S228C
Summary for 6CZ5
| Entry DOI | 10.2210/pdb6cz5/pdb |
| Descriptor | ATP-dependent RNA helicase DDX3X, 5'-O-[(R)-hydroxy(propanoylamino)phosphoryl]adenosine (2 entities in total) |
| Functional Keywords | inhibitor, dead-box protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 54512.55 |
| Authors | Barkovich, K.J.,Moore, M.K.,Hu, Q.,Shokat, K.M. (deposition date: 2018-04-08, release date: 2018-08-08, Last modification date: 2024-11-20) |
| Primary citation | Barkovich, K.J.,Moore, M.K.,Hu, Q.,Shokat, K.M. Chemical genetic inhibition of DEAD-box proteins using covalent complementarity. Nucleic Acids Res., 46:8689-8699, 2018 Cited by PubMed Abstract: DEAD-box proteins are an essential class of enzymes involved in all stages of RNA metabolism. The study of DEAD-box proteins is challenging in a native setting since they are structurally similar, often essential and display dosage sensitivity. Pharmacological inhibition would be an ideal tool to probe the function of these enzymes. In this work, we describe a chemical genetic strategy for the specific inactivation of individual DEAD-box proteins with small molecule inhibitors using covalent complementarity. We identify a residue of low conservation within the P-loop of the nucleotide-binding site of DEAD-box proteins and show that it can be mutated to cysteine without a substantial loss of enzyme function to generate electrophile-sensitive mutants. We then present a series of small molecules that rapidly and specifically bind and inhibit electrophile-sensitive DEAD-box proteins with high selectivity over the wild-type enzyme. Thus, this approach can be used to systematically generate small molecule-sensitive alleles of DEAD-box proteins, allowing for pharmacological inhibition and functional characterization of members of this enzyme family. PubMed: 30102385DOI: 10.1093/nar/gky706 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3 Å) |
Structure validation
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