User:Gabriel Zarzana Espinoza/Sandbox 1

This is a default text for your page Gabriel Zarzana Espinoza/Sandbox 1. Click above on edit this page to modify. Be careful with the < and > signs.

You may include any references to papers as in: the use of JSmol in Proteopedia ^[1] or to the article describing Jmol ^[2] to the rescue.

Function

The transforming growth factor beta 1 receptor is a protein that initiates the action signal of this factor by phosphorylating cytoplasmic proteins Smads at the C-terminus, causing these proteins to form a heteromeric complex. This complex will move to the nucleus to regulate the transcription of some specific genes of this factor, such as genes for: proliferation, differentiation, apoptosis or cell migration and the development of fibrosis in several organs, among others. This receptor is the product of the translation and transcription of the TGFBR1 gene, also known as ALK5, which is located on chromosome 9 of organisms belonging to the species Homo sapiens.

Structural highlights

This protein is an activin-type kinase receptor belonging to the heterotetrameric receptor complex, constituted by two of these and two beta 2 receptors, to which the transforming growth factor binds. This beta 1 receptor has a similar structure to that of the beta 2 receptor, with both being transmembrane serine/threonine kinase receptors and having: an extracellular cysteine-rich N-terminal domain involved in ligand binding; a transmembrane helix; and a C-terminal cytoplasmic kinase domain. In beta 1 receptors, the kinase domain, mostly an helix, adapts an anactive conformation, distorting and, thus, damaging the integrity of the ATP-binding site by constricting the phosphate and magnesium recognition pocket.

In its N-terminal, the beta 1 receptors possess a smaller N lobe, a larger C lobe and a GS region/domain. The N lobe, dominated by a twisted, five-stranded β sheet, is involved in ATP binding, but it also contains an insertion between strands β4 and β5 (the L45 loop, that extends out into solution to interact with other protein) that determines Smad substrate specificity. At the same time, the C lobe, largely helical (and, thus, why also called alfa C helix), is required for substrate recognition, while the GS region is a regulatory segment.

This segment is formed by the alfa GS1 helix, that is amphiphatic, and the alfa GS2 helix, that is the hydrophobic core of the protein. This second helix contacts both the beta sheet of N lobe and the first helix, which connects to the C lobe - thus, making the GS segment a region located between the thow lobes of the N-terminal. The conection of the two helices, in its turn, is made by a loop composed by a conserved sequence of 185TTSGSGSGLP194 (COLOCAR OS NÚMEROS PARA CIMA). This loop is the most important region of the beta 1 receptor, because it is this region that is phosphorylated in its serine and threonine residues by the beta 2 receptor of the heterotetrameric complex, when these is linked to the growth factor. Like that, the beta 1 receptor is activated and, in turn, transmits the factor signal, thus, phosphorylating, and so activating, Smad transcription factors. Studies claim that the substitution of the Thr residue of this loop with aspartate or glutamate turns the beta 1 receptor constitutively active, meaning it would not depend in phosphorylation by the beta 2 receptor to function.

(DETERMINAR ONDE SE LOCALIZA: PHOSPHATE BINDING LOOP, ACTIVATION SEGMENT AND CATALYTIC SEGMENT - POSSIVELMENTE, OU OS TRÊS SE LOCALIZAM NA REGIÃO TRANSMEMBRANA, OU APENAS O LOOP SE LOCALIZA LÁ E OS OUTROS DOIS NO TERMINAL C)

The activation segment of this protein is a beta hairpin composed by the strands beta 9 and beta 10, supported by the alfa F helix extension of the C-terminal. Together with beta 6, this activation segment forms a stranded sheet that stabilizes the rotated conformation of the C lobe. This stabilization is done by the van der Walls interactions and hidrogen bonds between C lobe/beta 6 and C lobe/beta 9, respectively. At the same time, it binds to beta 1 and beta 2 of the N lobe via van der Walls interactions

Disease

Small inhibitory molecules can block the catalytic activity of this protein by binding to its kinase through hydrogen bonds or hydrophobic interactions. These molecules, which generally have a central imidazole core with a pyridine ring, can be used on beta 1 receptors to reduce pathological fibrosis induced by it. Beta 1 receptor inhibitory substances can also be used to treat cancer (NEED REFERENCE FOR THIS).

This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.