MitoBloCK-10 is the first small molecule modulator to attenuate PAM (protein-associated motor) complex activity. It binds to a specific pocket in the C-terminal domain of Tim44 of the PAM complex.
A complex containing the integral membrane proteins Tim17 and Tim23 constitutes the import channel for preproteins containing amino-terminal hydrophilic presequences. This complex is associated with Tim44 which serves as an adaptor protein for the binding of mtHsp70 to the membrane. mtHsp70, a 70 kDa heat shock protein of the mitochondrial matrix, drives the ATP-dependent import reaction of the processed preprotein after cleavage of the presequence[2]. Tim44 is tightly associated with the inner mitochondrial membrane on the matrix side. The Tim44 C-Terminal Domain (CTD) functions as an Inner Mitochondrial Membrane (IMM) anchor that recruits the Presequence protein Associated Motor (PAM) to the TIM23 channel[3]. Tim44 plays multiple roles in mitochondrial protein import by recruiting Ssc1 and its J protein cochaperone to the translocon and coordinating their interactions to promote efficient protein translocation in vivo[4].Hsp70 chaperones interact with substrate proteins in a coordinated fashion that is regulated by nucleotides and enhanced by assisting cochaperones[5]. MitoBloCK-10 inhibits inner membrane(Tim)44 binding to the precursor and to Hsp70.MitoBloCK-10 is the first small molecule modulator to attenuate protein-associated motor (PAM) complex activity. MB-10 (100 μM) is a potential attenuator of protein import into mitochondria.MB-10 inhibits the import of substrates that use the TIM23 import pathway.MB-10 (0-100 μM) inhibits protein import into mammalian mitochondria[6].
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