New 'hook' for reversibly binding molecules to proteins
03 February 2010
UK chemists have found a simple new 'hook' that allows molecules to be attached to proteins and later removed, something that is currently difficult to achieve.
The system, based on well established interactions of the amino acid cysteine with maleimides, also gives an extra point of attachment so that two molecules can be snapped on to a single protein and later detached.
Attaching compounds to proteins, termed bioconjugation, has several important applications, such as allowing proteins to be tagged so that their fate can be followed in a cell. The amino acid cysteine has attractive chemistry for attaching 'linker' molecules such as the unsaturated imide maleimide. In turn, other compounds can be attached to the maleimide. However, the attachment is irreversible and in many situations it would be desirable to remove the bioconjugant - for example releasing it once it had reached a particular destination in the cell.
Now a team at University College London led by Stephen Caddick and James Baker has shown that modified maleimides can bind reversibly to proteins and also provide an extra hook for further molecules to be attached.
'We have made something that is very simple and very closely related to maleimide except that it contains halogen,' says Caddick. Maleimides contain a five membered ring, which becomes saturated when the molecule interacts with cysteine, making the reaction effectively irreversible. Bromomaleimides, however, retain a double bond within the ring when they couple with cysteine. This allows it to be reduced and to detach from the protein.
Reversibly linking a sugar to the cysteine thiol of a protein via dibromomaleimide
© J. Am. Chem. Soc.
Maleimide substituted with a single bromine results in a molecule with two points of attachment - one for the protein and one for the molecule to be attached. When two bromines are incorporated into the maleimide, a dibromomaleimide, an extra point of attachment is introduced. 'So you can attach the molecule to a cysteine residue of the protein and then have the capacity for two further molecules to be attached - a fluorescent dye and a peptide for example,' says Baker.
A key aspect to the system is that the bromomaleimide can detach under conditions found in the cytoplasm of the cell. 'This could provide a way to bring a prodrug into a cell,' says Caddick, 'where a compound requires detachment for the drug to become activated.'
Steve Archibald, who researches bioconjugation at the University of Hull in the UK, says the new approach 'is elegant and flexible - exactly that type of procedure that could find widespread use in protein modification. This is top quality science.'
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ReferencesM E B Smith et al, J. Am. Chem. Soc., 2010, DOI: 10.1021/ja908610s
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