PDBsum entry 4uip

Transferase

PDB id: 4uip

Contents

Protein chains

612 a.a.

238 a.a.

Ligands

NAG-NAG

NAG ×2

Waters ×41

PDB id:

4uip

Name:

Transferase

Title:

The complex structure of extracellular domain of egfr with repebody (rac1).

Structure:

Epidermal growth factor receptor. Chain: a. Fragment: residues 26-637. Synonym: proto-oncogenE C-erbb-1, receptor tyrosine-protein kinase e rbb-1. Engineered: yes. Repebody (rac1). Chain: b. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Listeria monocytogenes, synthetic construct, eptatretus burgeri. Organism_taxid: 1639, 32630, 7764. Expressed in: escherichia coli.

Resolution:

2.95Å R-factor: 0.240 R-free: 0.297

Authors:

Y.J.Kang,Y.J.Cha,H.S.Cho,J.J.Lee,H.S.Kim

Key ref:

J.J.Lee et al. (2015). Enzymatic prenylation and oxime ligation for the synthesis of stable and homogeneous protein-drug conjugates for targeted therapy. Angew Chem Int Ed Engl, 54, 12020-12024. PubMed id: 26315561 DOI: 10.1002/anie.201505964

Date:

31-Mar-15 Release date: 25-Nov-15

Protein chain

P00533  (EGFR_HUMAN) -  Epidermal growth factor receptor from Homo sapiens

Seq: 1210 a.a.

Struc: 612 a.a.

Protein chain

E0ACT6  (E0ACT6_LISMN) -  Internalin B (Fragment) from Listeria monocytogenes

Seq: 169 a.a.

Struc: 238 a.a.*

Protein chain

Q4G1L3  (Q4G1L3_EPTBU) -  Variable lymphocyte receptor B from Eptatretus burgeri

Seq: 305 a.a.

Struc: 238 a.a.*

* PDB and UniProt seqs differ at 134 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain A: E.C.2.7.10.1 - receptor protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺

L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] (Bound ligand (Het Group name = NAG) matches with 41.38% similarity) + ADP + H(+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1002/anie.201505964

Angew Chem Int Ed Engl 54:12020-12024 (2015)

PubMed id: 26315561

Enzymatic prenylation and oxime ligation for the synthesis of stable and homogeneous protein-drug conjugates for targeted therapy.

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.

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.