4MAO

RSK2 T493M C-Terminal Kinase Domain in Complex with RMM58

Summary for 4MAO

• Entry DOI: 10.2210/pdb4mao/pdb
• Related: 4M8T
• Descriptor: Ribosomal protein S6 kinase alpha-3, (2Z)-2-(1H-1,2,4-triazol-1-yl)-3-[3-(3,4,5-trimethoxyphenyl)-1H-indazol-5-yl]prop-2-enenitrile, SODIUM ION, ... (4 entities in total)
• Functional Keywords: protein kinase, phosphorylation, covalent inhibitor, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Mus musculus (mouse)
• Cellular location: Nucleus : P18654
• Total number of polymer chains: 1
• Total formula weight: 40523.04

Authors

Miller, R.M.,Taunton, J. (deposition date: 2013-08-16, release date: 2014-10-22, Last modification date: 2024-11-06)

Primary citation

Krishnan, S.,Miller, R.M.,Tian, B.,Mullins, R.D.,Jacobson, M.P.,Taunton, J.
Design of reversible, cysteine-targeted Michael acceptors guided by kinetic and computational analysis.
J.Am.Chem.Soc., 136:12624-12630, 2014

PubMed Abstract: Electrophilic probes that covalently modify a cysteine thiol often show enhanced pharmacological potency and selectivity. Although reversible Michael acceptors have been reported, the structural requirements for reversibility are poorly understood. Here, we report a novel class of acrylonitrile-based Michael acceptors, activated by aryl or heteroaryl electron-withdrawing groups. We demonstrate that thiol adducts of these acrylonitriles undergo β-elimination at rates that span more than 3 orders of magnitude. These rates correlate inversely with the computed proton affinity of the corresponding carbanions, enabling the intrinsic reversibility of the thiol-Michael reaction to be tuned in a predictable manner. We apply these principles to the design of new reversible covalent kinase inhibitors with improved properties. A cocrystal structure of one such inhibitor reveals specific noncovalent interactions between the 1,2,4-triazole activating group and the kinase. Our experimental and computational study enables the design of new Michael acceptors, expanding the palette of reversible, cysteine-targeted electrophiles.

PubMed: 25153195
DOI: 10.1021/ja505194w

Experimental method

X-RAY DIFFRACTION (2.6 Å)