Combinatorial Targeting of Common Docking and ATP Binding Sites on Mps1 MAPK for Management of Pathogenic Fungi

Zhiwei Kong; Saijie Li; Juxian Li; Yitong Chen; Meiqing Chen; Xin Zhang; Dongli Wang; Junfeng Liu

doi:10.1021/acs.jafc.4c09504

Combinatorial Targeting of Common Docking and ATP Binding Sites on Mps1 MAPK for Management of Pathogenic Fungi

J Agric Food Chem. 2024 Dec 2. doi: 10.1021/acs.jafc.4c09504. Online ahead of print.

Authors

Zhiwei Kong^{1

2}, Saijie Li^{1

2}, Juxian Li^{1

2}, Yitong Chen^{1

2}, Meiqing Chen^{1

2}, Xin Zhang², Dongli Wang², Junfeng Liu^{1

2

3}

Affiliations

¹ State Key Laboratory of Maize Bio-breeding, Joint International Research Laboratory of Crop Molecular Breeding, China Agricultural University, Beijing 100193, China.
² Ministry of Agriculture Key Laboratory for Crop Pest Monitoring and Green Control, College of Plant Protection, China Agricultural University, Beijing 100193, China.
³ Sanya Institute of China Agricultural University, Sanya 572024, China.

PMID: 39622772
DOI: 10.1021/acs.jafc.4c09504

Abstract

Resistance in pathogenic fungi necessitates the development of fungicides with new mechanisms of action. The Mps1 MAPK of Magnaporthe oryzae, the pathogen of rice blast disease, has been shown to be a molecular target for fungicide research. Here, we present compound TAK-733 that interacts with the common docking (CD) site of Mps1 and can be used in combination with ATP-competitive inhibitors. We initially identified compounds PLX-4720 and TAK-733 that interact with Mps1. Subsequent assays show that PLX-4720 is an ATP-competitive inhibitor, whereas TAK-733 binds to the CD site of Mps1─an interaction site for its MAPKK─but not to the ATP-binding pocket as it does in the kinase MEK1. In vivo assays demonstrated that TAK-733 exhibits combinational effects with ATP-competitive inhibitors PLX-4720 and A378-0. Collectively, we present TAK-733 as having a new mechanism of action suitable for combinational application with ATP-competitive inhibitors in the management of pathogenic fungi.

Keywords: CD site; MAPK; Magnaporthe oryzae; combination; inhibitor.