Synthetic ligands for apo-neocarzinostatin.
Neocarzinostatin (NCS) is a 1:1 complex of an enediyne chromophore (NCSChrom), non-covalently bound to an 11 kDa protein (apoNCS). We are exploring apoNCS as a generic protein system for sequestering small molecules for therapeutic applications. Here, we disclose a new flavone ligand 1 for apoNCS and present a high-resolution NMR structure of this ligand bound to apoNCS. This is the first high-resolution structure of a completely non-cognate ligand bound to the apoNCS protein. This work provides unambiguous evidence that a completely new class of ligand can bind specifically to apoNCS. Furthermore, the mode of binding is different than that of the naphthoate-based ligands, and for such a simple hydrophobic compound, the new ligand surprisingly binds specifically. This work indicates that apo-Neocarzinostatin has multiple selective and distinct binding modes for small-molecule cargo.
Department of Chemistry, University College London, UK. s.caddick@ucl.ac.uk
Stephen
S
Caddick
Frederick W
FW
Muskett
Rhys G
RG
Stoneman
Derek N
DN
Woolfson
D001059:Apoproteins / Q000737:chemistry* / Q000378:metabolism; D047309:Flavones / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D009353:Zinostatin / Q000737:chemistry* / Q000378:metabolism
D001059:Apoproteins; D047309:Flavones; D008024:Ligands; C052401:aponeocarzinostatin; D009353:Zinostatin