Binding Mode of Human Norepinephrine Transporter Interacting with HIV-1 Tat
| Autor: | Sarah Elizabeth B Davis, Yaxia Yuan, Ciai Lin, Chang-Guo Zhan, Charles A. Adeniran, Jun Zhu, Jiahui Xu |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Molecular model
Physiology Dopamine Cognitive Neuroscience HIV Infections Biochemistry Article Protein–protein interaction Norepinephrine 03 medical and health sciences 0302 clinical medicine medicine Humans 030304 developmental biology Dopamine transporter Dopamine Plasma Membrane Transport Proteins 0303 health sciences Norepinephrine Plasma Membrane Transport Proteins biology Chemistry Mutagenesis virus diseases Transporter Cell Biology General Medicine Monoamine neurotransmitter Norepinephrine transporter HIV-1 Mutagenesis Site-Directed Biophysics biology.protein 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | ACS Chem Neurosci |
| ISSN: | 1948-7193 |
| Popis: | The increase of HIV infection in macrophages results in HIV proteins being released, like HIV Tat which impairs the function of monoamine transporters. HIV-infected patients have displayed increased synaptic levels of dopamine (DA) due to reduced binding and function of monoamine transporters such as the norepinephrine transporter (NET) and the dopamine transporter (DAT). Development of a three-dimensional model of the HIV-1 Tat-human NET (hNET) binding complex would help reveal how HIV-1 Tat causes toxicity in the neuron by affecting DA uptake. Here we use computational techniques such as molecular modeling to study microscopic properties and molecular dynamics of the HIV-1 Tat-hNET binding. These modeling techniques allow us to analyze noncovalent interactions and observe residue-residue contacts to verify a model structure. The modeling results studied here show that HIV-1 Tat-hNET binding is highly dynamic and that HIV-1 Tat preferentially binds to hNET in its outward-open state. In particular, HIV-1 Tat forms hydrogen bond interactions with side chains of hNET residues Y84, K88, and T544. The favorable hydrogen bonding interactions of HIV-1 Tat with the hNET side chain residues Y84 and T544 have been validated by our subsequently performed DA uptake activity assays and site-directed mutagenesis, suggesting that the modeled HIV-1 Tat-hNET binding mode is reasonable. These mechanistic and structural insights gained through homology models discussed in this study are expected to encourage the pursuit of pharmacological and biochemical studies on HIV-1 Tat interacting with hNET mechanisms and detailed structures. |
| Databáze: | OpenAIRE |
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