Difference between revisions of "Part:BBa K5267001"

Revision as of 08:58, 22 September 2024

Mammalian MT1 melatonin receptor, Gi-coupled GPCR.

The mammalian MT1 melatonin receptor is a G protein-coupled receptor (GPCR) primarily coupled to the Gi/o protein family. This receptor plays a crucial role in regulating circadian rhythms and sleep-wake cycles by responding to melatonin, a hormone produced by the pineal gland. The MT1 receptor has a seven-transmembrane domain structure characteristic of GPCRs and is involved in inhibiting adenylate cyclase activity, leading to decreased levels of cAMP. It also participates in other signaling pathways, including the activation of phospholipase C and the regulation of intracellular calcium levels. Structural studies of MT1 reveal unique features such as a "lid-like" structure in the extracellular loop 2 (ECL2) that influences ligand binding and selectivity. This part is essential for projects involving the study of circadian biology, sleep regulation, and the pharmacological targeting of melatonin receptors.

Usage and Biology

This part of gene encodes one of two high affinity forms of a receptor for melatonin, the primary hormone secreted by the pineal gland. This receptor is a G-protein coupled, 7-transmembrane receptor, a rhodopsin-like class A receptor that is responsible for melatonin effects on mammalian circadian rhythm and reproductive alterations affected by day length. The receptor is an integral membrane protein that is resadily detectable and localized to two specific regions of the brain. The hypothalamic suprachiasmatic nucleus appears to be involved in circadian rhythm while the hypophysial pars tuberalis may be responsible for the reproductive effects of melatonin.[1] In the human body, melatonin (N-acetyl-5-methoxytryptamine) is a widespread neurohormone with roles in circadian rhythm regulation, antioxidative protection and several other functions. It binds to the ligand binding pocket of melatonin receptor with high affinity in the human body.[2] The figure from Okamoto, H. H., Cecon, E., Nureki, O., Rivara, S., & Jockers, R. (2024) shows the overall structure of MT1, both activated structure and inactivated structure, and the position of the ligand binding pocket of MT1, where allows melatonin binds to it and activate of downstream gene pathways.[2]

Figure: Overall structures of MT1 (A: inactive state [PDB ID: 6ME2], H: active state [PDB ID: 7DB6]), J: active state [PDB ID: 7VH0]). (B) Top view (left) and side view (right) of MT1 in an inactive state [PDB ID: 6ME2]. (C) Overall TM6 movement during receptor activation of MT1 (inactive state: [PDB ID: 6ME2] and active state: [PDB ID: 7DB6]). (E) Ligand binding site of crystal structures of MT1 (left top: [PDB ID: 6ME2], left bottom: [PDB ID: 6ME3], right top: [PDB ID: 6ME4], right bottom: [PDB ID: 6ME5]). (I) Ligand binding site of cryo‐EM structures of MT1 (left: [PDB ID: 7DB6], middle: [PDB ID: 7VGY], right: [PDB ID: 7VGZ]).[2] [2] Figure: (A) Overview of structural changes during activation of MT1 (inactive state: [PDB ID: 6ME2], active state: [PDB ID: 7DB6]). (B) Conformational changes from the ligand binding site to the PIF motif. (C) Conformational changes from the Na+ binding site to the DRY (NRY in MTRs) motif.[2] The MTNR1a part is cloned after the PGK promotor and before the bGH polyA sequence in the frame of Sleeping Beauty transposable element. After transfection into HEK293 cells, the P_PGK->MTNR1a->BGH polyA device could stably exist in the genome of HEK293 cells.

Sequence and Features