PDBsum entry 5tym

Hydrolase/hydrolase inhibitor

PDB id: 5tym

Contents

Protein chain

566 a.a.

Ligands

7NS

Waters ×117

PDB id:

5tym

Name:

Hydrolase/hydrolase inhibitor

Title:

Alpha-esterase-7 in complex with [3-bromo-5-(pyrrolidin-1-yl) phenyl]borinic acid

Structure:

Carboxylic ester hydrolase. Chain: a. Engineered: yes. Mutation: yes

Source:

Lucilia cuprina. Green bottle fly. Organism_taxid: 7375. Gene: lcae7. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

1.84Å R-factor: 0.231 R-free: 0.287

Authors:

G.J.Correy,C.J.Jackson

Key ref:

G.J.Correy et al. (2019). Overcoming insecticide resistance through computational inhibitor design. Proc Natl Acad Sci U S A, 116, 21012-21021. PubMed id: 31575743 DOI: 10.1073/pnas.1909130116

Date:

21-Nov-16 Release date: 06-Dec-17

Protein chain

Q25252  (Q25252_LUCCU) -  Carboxylic ester hydrolase from Lucilia cuprina

Seq: 570 a.a.

Struc: 566 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.1.1.- - ?????

DOI no: 10.1073/pnas.1909130116

Proc Natl Acad Sci U S A 116:21012-21021 (2019)

PubMed id: 31575743

Overcoming insecticide resistance through computational inhibitor design.

G.J.Correy, D.Zaidman, A.Harmelin, S.Carvalho, P.D.Mabbitt, V.Calaora, P.J.James, A.C.Kotze, C.J.Jackson, N.London.

ABSTRACT

Insecticides allow control of agricultural pests and disease vectors and are vital for global food security and health. The evolution of resistance to insecticides, such as organophosphates (OPs), is a serious and growing concern. OP resistance often involves sequestration or hydrolysis of OPs by carboxylesterases. Inhibiting carboxylesterases could, therefore, restore the effectiveness of OPs for which resistance has evolved. Here, we use covalent virtual screening to produce nano-/picomolar boronic acid inhibitors of the carboxylesterase αE7 from the agricultural pest Lucilia cuprina as well as a common Gly137Asp αE7 mutant that confers OP resistance. These inhibitors, with high selectivity against human acetylcholinesterase and low to no toxicity in human cells and in mice, act synergistically with the OPs diazinon and malathion to reduce the amount of OP required to kill L. cuprina by up to 16-fold and abolish resistance. The compounds exhibit broad utility in significantly potentiating another OP, chlorpyrifos, against the common pest, the peach-potato aphid (Myzus persicae). These compounds represent a solution to OP resistance as well as to environmental concerns regarding overuse of OPs, allowing significant reduction of use without compromising efficacy.