Proximity-driven metallopeptide catalysis: Remarkable side-chain scope enables modification of the Fos bZip domain

Abstract

Coiled-coil assembly of substrate peptides with dirhodium metallopeptide catalysts enables side-chain modification on the basis of molecular shape. A wide range of amino acids are effectively modified, including the first examples of carboxamide (glutamine and asparagine) modification. The method is used to achieve covalent modification of the c-Fos bZip domain at different residues, depending on the metallopeptide structure. By combining promiscuous catalytic reactivity with specific molecular recognition, this work establishes a general strategy for protein modification on the basis of molecular shape. A broad range of peptide-protein interactions are potentially amenable to this approach.

Protein Design: Toward Functional Metalloenzymes

“…Despite a significantly decreased affinity for c-Fos, Jun(Rh 2 ) catalyzes the modification of the targeted Gln residue yielding 88% conversion at −15 °C. 998 This example establishes the ability of templated modification to succeed, even in cases of transient assembly because the affinity between the catalyst and substrate is very low. Further, dirhodium-containing metallopeptides, with designs based on the MDM2-binding domain of p53, were found to inhibit MDM2.…”

Designing Enzyme-Like Catalysts: A Rhodium(II) Metallopeptide Case Study

“…Turnover numbers of up to 50 were obtained at micromolar substrate concentration, and the rate enhancement for complementary substrates relative to an unstructured control reaction was >10 3 . Even more powerfully, the proximity-driven catalysis enabled modification of many other side chains (Figure 1) that are completely unreactive with simple [1,2]. rhodium catalysts such as Rh2(OAc)4.…”

“…Treatment with stabilized diazo reagents resulted in clean modification of position "g" on the corresponding substrate helix, immediately flanking the rhodium center. The site of location was established by MS/MS fragmentation methods [1,2] and NMR with isotopically-labeled diazo reagents. Tryptophan was the most reactive side chain.…”

The Outer-Coordination Sphere: Incorporating Amino Acids and Peptides as Ligands for Homogeneous Catalysts to Mimic Enzyme Function

“…The clear advantage of this work is that peptides can be used without elaborate chemical modification. To date, much of this work has focused on enantioselectivity (140,141), while also exploring the potential for biocompatibility (136,142). Of particular note is the ability of the dirhodium catalysts to stabilize 3 10 -helices or α-helices by including carboxylates in the side chains at the i→ i+3 or i→ i+4 residues, respectively.…”