5NAL

The crystal structure of inhibitor-15 covalently bound to PDE6D

Summary for 5NAL

• Entry DOI: 10.2210/pdb5nal/pdb
• Descriptor: Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit delta, ~{N}4-[(4-chlorophenyl)methyl]-~{N}1-(cyclohexylmethyl)-~{N}4-cyclopentyl-~{N}1-[(~{Z})-4-[(~{E})-methyliminomethyl]-5-oxidanyl-hex-4-enyl]benzene-1,4-disulfonamide (3 entities in total)
• Functional Keywords: lipid binding protein, woodward's reagent k, covalent protein labeling at glutamic acids, arl2 mediated cargo release
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm, cytosol : O43924
• Total number of polymer chains: 1
• Total formula weight: 18105.31

Authors

Fansa, E.K.,Martin-Gago, P.,Waldmann, H.,Wittinghofer, A. (deposition date: 2017-02-28, release date: 2017-05-10, Last modification date: 2024-10-23)

Primary citation

Martin-Gago, P.,Fansa, E.K.,Winzker, M.,Murarka, S.,Janning, P.,Schultz-Fademrecht, C.,Baumann, M.,Wittinghofer, A.,Waldmann, H.
Covalent Protein Labeling at Glutamic Acids.
Cell Chem Biol, 24:589-597.e5, 2017

PubMed Abstract: Covalent labeling of amino acids in proteins by reactive small molecules, in particular at cysteine SH and lysine NH groups, is a powerful approach to identify and characterize proteins and their functions. However, for the less-reactive carboxylic acids present in Asp and Glu, hardly any methodology is available. Employing the lipoprotein binding chaperone PDE6δ as an example, we demonstrate that incorporation of isoxazolium salts that resemble the structure and reactivity of Woodward's reagent K into protein ligands provides a novel method for selective covalent targeting of binding site carboxylic acids in whole proteomes. Covalent adduct formation occurs via rapid formation of enol esters and the covalent bond is stable even in the presence of strong nucleophiles. This new method promises to open up hitherto unexplored opportunities for chemical biology research.

PubMed: 28434875
DOI: 10.1016/j.chembiol.2017.03.015

Experimental method

X-RAY DIFFRACTION (2.2 Å)