Protein-small molecule interactions in neocarzinostatin, the prototypical enediyne chromoprotein antibiotic.
The enediyne chromoproteins are a class of potent antitumour antibiotics comprising a 1:1 complex of a protein and a noncovalently bound chromophore. The protein is required to protect and transport the highly labile chromophore, which acts as the cytotoxic component by reacting with DNA leading to strand cleavage. A derivative of the best-studied member of this class, neocarzinostatin (NCS), is currently in use as a chemotherapeutic in Japan. The application of the chromoproteins as therapeutics along with their unique mode of action has prompted widespread interest in this area. Notable developments include the discovery of non-natural ligands for the apoproteins and the observation that multiple binding modes are available for these ligands in the binding site. Mutation studies on the apoproteins have revealed much about their stability and variability, and the application of an in vitro evolution method has conferred new binding specificity for unrelated ligands. These investigations hold great promise for the application of the apoproteins for drug-delivery, transport and stabilisation systems.
Baker
James R
JR
University College London, Department of Chemistry, Christopher Ingold Laboratories, 20 Gordon Street, London, WC1H 0AJ, UK.
Woolfson
Derek N
DN
Muskett
Frederick W
FW
Stoneman
Rhys G
RG
Urbaniak
Michael D
MD
Caddick
Stephen
S
D000900:Anti-Bacterial Agents / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D015335:Molecular Probes; D009154:Mutation; D011506:Proteins / Q000737:chemistry* / Q000235:genetics; D009353:Zinostatin / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D008024:Ligands; D015335:Molecular Probes; D011506:Proteins; D009353:Zinostatin