Molecular Interactions of Zinc with the Glycine Receptor

نویسنده

  • Paul Steven Miller
چکیده

The ionotropic receptors including nicotinic acetylcholine (nAChR), y-aminobutyric acid type A and C (G A B A a/c), serotonin (5HT-3) and glycine receptors (GlyR) all comprise the cys-loop receptor family. A pentameric configuration is adopted by these receptors featuring a large extra cellular domain, four transmembrane (M) spanning domains and an intracellular compartment primarily contributed from the M3-4 loop. The recent advent of an X-ray crystal structure of the related ACh binding protein from snail, Lymnaea stagnalis, and an electron micrograph nearing atomic resolution of the transmembrane domains for the Torpedo nAChR provide the opportunity to homology model the structures of all cys-loop ligand-gated receptors and investigate critical elements of receptor function with unprecedented accuracy. By using homology modelling to guide site-directed mutagenesis in combination with whole-cell patch clamp electrophysiology, molecular elements that mediate the biphasic modulation of glycine receptors by Zn2* were investigated. The structure of a previously identified low sensitivity inhibitory Zn2+ site was clarified revealing critical determinants of GlyR subtype selectivity for Zn2* mediated inhibition. Intriguingly these experiments also revealed a novel functional asymmetry at this site suggesting that one specific side of the site directs downstream transduction of the inhibitory Zn2̂ effect. This enabled the elucidation of a hydrophobic pathway leading directly through the core of the GlyR from the inhibitory Zn2+ site to the agonist binding site suggesting a mechanism for Zn2* mediated inhibition. This study also investigated the structural basis for Zn2* enhancement of GlyR function. A comparative study of GlyR a l and a2 followed by a directed mutagenesis regional scan led to the identification of a complete and novel site for Zn2+ potentiation. Further studies also elucidated a potential mechanism of action for this site by identifying an important gating component of the GlyR, which exhibited a strong interaction with this novel potentiation site for Zn2+.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Molecular Insight into the Mutual Interactions of Two Transmembrane Domains of Human Glycine Receptor (TM23-GlyR), with the Lipid Bilayers

Appearing as a computational microscope, MD simulation can ‘zoom in’ to atomic resolution to assess detailed interactions of a membrane protein with its surrounding lipids, which play important roles in the stability and function of such proteins. This study has employed the molecular dynamics (MD) simulations, to determine the effect of added DMPC or DMTAP molecules on the structure of D...

متن کامل

Molecular Docking Based on Virtual Screening, Molecular Dynamics and Atoms in Molecules Studies to Identify the Potential Human Epidermal Receptor 2 Intracellular Domain Inhibitors

Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Overexpression of HER2 usually causes malignant transformation of cells and is responsible for the breast cancer. In this work, the virtual screening, molecular docking, quantum mechanics and molecular dynamics methods were employed to study protein–ligand ...

متن کامل

Modeling and interactions analysis of the novel antagonist agent flibanserin with 5-hydroxytryptamine 2A (5-HT2A) serotonin receptor as a HSDD treatment in premenopausal women

Flibanserin is a novel antagonist small molecule to treat the hypoactive sexual desire disorder (HSDD) in the premenopausal women. The present article is related to the structural and electronic properties study and docking analysis of the title compound with 5-hydroxytryptamine 2A (5-HT2A) serotonin receptor. To access these aims, the molecular structure of the said compound was optimized usin...

متن کامل

Interactions between Zinc and Allosteric Modulators of the Glycine Receptor.

The glycine receptor is a pentameric ligand-gated ion channel that is involved in fast inhibitory neurotransmission in the central nervous system. Zinc is an allosteric modulator of glycine receptor function, enhancing the effects of glycine at nanomolar to low-micromolar concentrations and inhibiting its effects at higher concentrations. Low-nanomolar concentrations of contaminating zinc in el...

متن کامل

Molecular docking study of Papaver alkaloids to some alkaloid receptors

Background and objectives: More than 40 different alkaloids have been obtained from opium the most important of which are morphine, codeine, papaverine, noscapine and tabaine. Opioid alkaloids produce analgesia by affecting areas of the brain that have peptides with pharmacological pseudo-opioid properties. These alkaloids show important effects on some intracellular peptides l...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره   شماره 

صفحات  -

تاریخ انتشار 2013