Structural Rationale for the Coupled Binding and Unfolding of the c-Myc Oncoprotein by Small Molecules

Abstract

The basic-helix-loop-helix-leucine-zipper domains of the c-Myc oncoprotein and its obligate partner Max are intrinsically disordered (ID) monomers that undergo coupled folding and binding upon heterodimerization. We have identified the binding sites and determined the structural means by which two unrelated small molecules, 10058-F4 and 10074-G5, bind c-Myc and stabilize the ID monomer over the highly ordered c-Myc-Max heterodimer. In solution, the molecules bind to distinct regions of c-Myc and thus limit its ability to interact with Max and assume a more rigid and defined conformation. The identification of multiple, specific binding sites on an ID domain suggests that small molecules may provide a general means for manipulating the structure and function of ID proteins, such as c-Myc.

Mitoxantrone Binds to Nopp140, an Intrinsically Unstructured Protein, and Modulate its Interaction with Protein Kinase CK2

“…Previously, we have shown that doxorubicin could bind to the C-terminal half of unphosphorylated form of Nopp140 with apparent K D of 4.5 × 10 −6 M, 14 and lowered its level of CK2-dependent phosphorylation of Nopp140. 9 The interaction between IUPs and small molecules that bind to IUP had also been reported by Follis et al 42 The intrinsically disordered regions of cMyc and Max interacted with each other forming a helical heterodimer. Small molecules that interrupted this interaction 43 were shown to interact with the intrinsically disordered region of c-Myc and induced helical conformation.…”

Intrinsically Disordered Proteins as Drug Targets

“…[18][19][20] The order-disordered transitions suffered by IDPs can be produced by several factors such as exogenous perturbations (for instance pH, [21][22][23] Tª 22,[24][25][26] or macromolecular crowding) 23,[27][28][29][30] or binding (multiple) diverse molecular entities, such as proteins 18,31,32 or small molecules. 10,[33][34][35] As they are very promiscuous molecules, IDPs can bind multiple partners. 14 The conformational flexibility showed by IDPs is key to understand their behavior.…”

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“…or binding (multiple) diverse molecular entities, such as proteins [18,31,32]. or small molecules [10,[33][34][35]. As they are very promiscuous molecules, IDPs can bind multiple partners [14].…”