PDBsum entry 4uip

Transferase

PDB id: 4uip

Contents

Protein chains

612 a.a.

238 a.a.

Ligands

NAG-NAG

NAG ×2

Waters ×41

References listed in PDB file

Key reference

• Title: Enzymatic prenylation and oxime ligation for the synthesis of stable and homogeneous protein-Drug conjugates for targeted therapy.
• Authors: J.J.Lee, H.J.Choi, M.Yun, Y.Kang, J.E.Jung, Y.Ryu, T.Y.Kim, Y.J.Cha, H.S.Cho, J.J.Min, C.W.Chung, H.S.Kim.
• Ref.: Angew Chem Int Ed Engl, 2015, 54, 12020-12024. [DOI no: 10.1002/anie.201505964]
• PubMed id: 26315561

Abstract

Targeted therapy based on protein-drug conjugates has attracted significant attention owing to its high efficacy and low side effects. However, efficient and stable drug conjugation to a protein binder remains a challenge. Herein, a chemoenzymatic method to generate highly stable and homogenous drug conjugates with high efficiency is presented. The approach comprises the insertion of the CaaX sequence at the C-terminal end of the protein binder, prenylation using farnesyltransferase, and drug conjugation through an oxime ligation reaction. MMAF and an EGFR-specific repebody are used as the antitumor agent and protein binder, respectively. The method enables the precisely controlled synthesis of repebody-drug conjugates with high yield and homogeneity. The utility of this approach is illustrated by the notable stability of the repebody-drug conjugates in human plasma, negligible off-target effects, and a remarkable antitumor activity in vivo. The present method can be widely used for generating highly homogeneous and stable PDCs for targeted therapy.