Assessing the role of residue Phe108 of cytochrome P450 3A4 in allosteric effects of midazolam metabolism

Fu, Tingting; Zhang, Hongxing; Zheng, Qingchuan

doi:10.1039/d3cp05270b

Phys. Chem. Chem. Phys.

2024

DOI: 10.1039/d3cp05270b

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Assessing the role of residue Phe108 of cytochrome P450 3A4 in allosteric effects of midazolam metabolism

Tingting Fu,

Hongxing Zhang,

Qingchuan Zheng

Abstract: Residue F108 of CYP3A4 is closely related to substrate binding stability, the transition of substrate binding mode, and the characteristics of CYP3A4 channels, playing an important role in MDZ metabolism and allosteric effects.

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Structural Models of Human Norepinephrine Transporter Ensemble Reveal the Allosteric Sites and Ligand-Binding Mechanism

Luo,

Zhang,

et al. 2024

J. Phys. Chem. B

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The norepinephrine transporter (NET) plays a pivotal role in recycling norepinephrine (NE) from the synaptic cleft. However, the structures referring to the conformational heterogeneity of NET during the transport cycle remain poorly understood. Here, three structural models of NE bound to the orthosteric site of NET in outward-open (OO holo ), outward-occluded (OC holo ), and inward-open (IO holo ) conformations were first obtained using the multistate structures of serotonin transporter as templates and further characterized through Gaussian-accelerated molecular dynamics and free energy reweighting. Analysis of the structures revealed eight potential allosteric sites on the functional-specific states of NET. One of the pharmacologically relevant pockets located at the extracellular vestibule was further verified by simulating the binding behaviors of a clinical trial drug χ-MrIA that is allosterically regulating NET. These structural and energetic insights into NET advanced our understanding of NE reuptake and paved the way for discovering novel molecules targeting the allosteric sites.

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Structural Models of Human Norepinephrine Transporter Ensemble Reveal the Allosteric Sites and Ligand-Binding Mechanism

Luo,

Zhang,

et al. 2024

J. Phys. Chem. B

View full text Add to dashboard Cite

show abstract

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Assessing the role of residue Phe108 of cytochrome P450 3A4 in allosteric effects of midazolam metabolism

Abstract: Residue F108 of CYP3A4 is closely related to substrate binding stability, the transition of substrate binding mode, and the characteristics of CYP3A4 channels, playing an important role in MDZ metabolism and allosteric effects.

Cited by 1 publication

References 46 publications

Structural Models of Human Norepinephrine Transporter Ensemble Reveal the Allosteric Sites and Ligand-Binding Mechanism

Structural Models of Human Norepinephrine Transporter Ensemble Reveal the Allosteric Sites and Ligand-Binding Mechanism

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