Summary for 9AUU
| Entry DOI | 10.2210/pdb9auu/pdb |
| Descriptor | Heat shock protein HSP 90-alpha, 3-{[(3R)-3-({6-amino-8-[(6-iodo-2H-1,3-benzodioxol-5-yl)sulfanyl]-9H-purin-9-yl}methyl)piperidin-1-yl]methyl}-6-fluoro-2-hydroxybenzaldehyde, MAGNESIUM ION, ... (4 entities in total) |
| Functional Keywords | inhibitor, covalent, chaperone |
| Biological source | Homo sapiens (human) |
| Total number of polymer chains | 1 |
| Total formula weight | 27214.41 |
| Authors | Weaver, J.M.,Craven, G.B.,Taunton, J. (deposition date: 2024-02-29, release date: 2024-10-16, Last modification date: 2024-10-23) |
| Primary citation | Weaver, J.,Craven, G.B.,Tram, L.,Chen, H.,Taunton, J. Aminomethyl Salicylaldehydes Lock onto a Surface Lysine by Forming an Extended Intramolecular Hydrogen Bond Network. J.Am.Chem.Soc., 146:24233-24237, 2024 Cited by PubMed Abstract: The development of electrophilic ligands that rapidly modify specific lysine residues remains a major challenge. Salicylaldehyde-based inhibitors have been reported to form stable imine adducts with the catalytic lysine of protein kinases. However, the targeted lysine in these examples is buried in a hydrophobic environment. A key unanswered question is whether this strategy can be applied to a lysine on the surface of a protein, where rapid hydrolysis of the resulting salicylaldimine is more likely. Here, we describe a series of aminomethyl-substituted salicylaldehydes that target a fully solvated lysine on the surface of the ATPase domain of Hsp90. By systematically varying the orientation of the salicylaldehyde, we discovered ligands with long residence times, the best of which engages Hsp90 in a quasi-irreversible manner. Crystallographic analysis revealed a daisy-chain network of intramolecular hydrogen bonds in which the salicylaldimine is locked into position by the adjacent piperidine linker. This study highlights the potential of aminomethyl salicylaldehydes to generate conformationally stabilized, hydrolysis-resistant imines, even when the targeted lysine is far from the ligand binding site and is exposed to bulk solvent. PubMed: 39177126DOI: 10.1021/jacs.4c04314 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2 Å) |
Structure validation
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