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2- and N6-functionalized adenosine-5'-diphosphate analogs for the inhibition of mortalin.


ABSTRACT: Our early efforts to find a covalent inhibitor of mortalin, a member of the 70 kD heat shock protein (Hsp70) family, led us to solve the structure of the mortalin nucleotide-binding domain (NBD) in complex with N6-propargyladenosine-5'-diphosphate. The acquired structure emphasizes the ability of the nucleotide-binding pocket to accommodate modified ADP compounds. A library of ADP analogs modified at either the 2- or N6-positions of adenosine was screened against the mortalin-NBD. Competitive inhibition and binding assays of the analogs demonstrate that modifications at the 2- or N6-positions have potential to bind and inhibit mortalin uniquely compared to other Hsp70 homologs, and that modifications at the 2-position confer the greatest selectivity in binding and inhibition of the mortalin-NBD.

SUBMITTER: Moseng MA 

PROVIDER: S-EPMC6690775 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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2- and N6-functionalized adenosine-5'-diphosphate analogs for the inhibition of mortalin.

Moseng Mitchell A MA   Nix Jay C JC   Page Richard C RC  

FEBS letters 20190618 15


Our early efforts to find a covalent inhibitor of mortalin, a member of the 70 kD heat shock protein (Hsp70) family, led us to solve the structure of the mortalin nucleotide-binding domain (NBD) in complex with N6-propargyladenosine-5'-diphosphate. The acquired structure emphasizes the ability of the nucleotide-binding pocket to accommodate modified ADP compounds. A library of ADP analogs modified at either the 2- or N6-positions of adenosine was screened against the mortalin-NBD. Competitive in  ...[more]

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