7XHY

Crystal structure of MerTK Kinase domain with BMS794833

Summary for 7XHY

• Entry DOI: 10.2210/pdb7xhy/pdb
• Descriptor: Tyrosine-protein kinase Mer, ~{N}-[4-(2-azanyl-3-chloranyl-pyridin-4-yl)oxy-3-fluoranyl-phenyl]-5-(4-fluorophenyl)-4-oxidanylidene-1~{H}-pyridine-3-carboxamide, CHLORIDE ION, ... (5 entities in total)
• Functional Keywords: atp competitive inhibitor mertk-bms794833 complex, transferase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 35070.54

Authors

Kim, J.H.,Lee, B.I. (deposition date: 2022-04-11, release date: 2022-11-30, Last modification date: 2023-11-29)

Primary citation

Bae, S.H.,Kim, J.H.,Park, T.H.,Lee, K.,Lee, B.I.,Jang, H.
BMS794833 inhibits macrophage efferocytosis by directly binding to MERTK and inhibiting its activity.
Exp.Mol.Med., 54:1450-1460, 2022

PubMed Abstract: Myeloid epithelial reproductive proto-oncogene tyrosine kinase (MERTK) plays an essential role in modulating cancer immune tolerance by regulating macrophage efferocytosis. Studies are underway to develop small-molecule chemicals that inhibit MERTK as cancer immunotherapeutic agents, but these efforts are in their early stages. This study identified BMS794833, whose primary targets are MET and VEGFR2, as a potent MERTK inhibitor and developed a real-time efferocytosis monitoring system. The X-ray cocrystal structure revealed that BMS794833 was in contact with the ATP-binding pocket and the allosteric back pocket, rendering MERTK inactive. Homogeneous time-resolved fluorescence kinetic and Western blotting analyses showed that BMS794833 competitively inhibited MERTK activity in vitro and inhibited the autophosphorylation of MERTK in macrophages. We developed a system to monitor MERTK-dependent efferocytosis in real time, and using this system, we confirmed that BMS794833 significantly inhibited the efferocytosis of differentiated macrophages. Finally, BMS794833 significantly inhibited efferocytosis in vivo in a mouse model. These data show that BMS794833 is a type II MERTK inhibitor that regulates macrophage efferocytosis. In addition, the real-time efferocytosis monitoring technology developed in this study has great potential for future applications.

PubMed: 36056187
DOI: 10.1038/s12276-022-00840-x

Experimental method

X-RAY DIFFRACTION (2.16 Å)