This is a default text for your page Steve Klimcak/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.

Introduction

Structure

domains

This is the

Active Site

Function

Mechanism

The demethylation of lysine via LSD1 occurs through oxidation via a hydride transfer. Shown in Figure 2 the first step involves the initiating a hydride transfer from the one of the two methyl groups bound to the nitrogen at the lysine tail, via a N5 on the flavin group. An imine cation is then formed at the end of the lysine tail to compensate for the loss of hydride. The FAD co-factor is also negatively charged and lysine residue 661 provides stability by drawing that charge away. In the next step the imine is hydrolyzed and transitions to an hemiaminal. This then breaks down to formaldehyde and the product lysine.

Figure 2

Hydrophobic Pocket

The hydrophobic pocket located in the active site cavity of LSD1, forms a catalytic chamber where the substrate lysine is oriented and positioned to interact with the FAD co-factor to initiate demethylation. The specific residues making up the pocket include valine-317, glycine-330, alanine-331, methionine 332, valine-333, phenylalanine-338, leucine-569, asparagine-660, lysine-661, tryptophan 695, serine 749, serine 760, and tyrosine-761. These residues in the shown in green surrounds the FAD in a way such that it exposes the catalytic nitrogen(N5) that is responsible for the two electron demethylation. The depicted as a sphere is approximately 3.5Å away from the substrate lysine. Lysine 661 shown 4.98Å is responsible for anchoring the FAD in place to efficiently bind the substrate lysine. Another three seperate pockets help bind the histone tail residues to the substrate lysine which is essential for identifying different modifications of the histone tail.

Application

LSD1 plays a pivital role in many biological processes such as cell growth, epithelial-mesenchymal transition, stem cell biology, malignant transformation of cells, and cell differentiation. Malfunctioning of these activities can lead to life threatening diseases such as acute myeloid leukemia and acute lymphoblastic leukemia. Evidence has shown that these activities have ties to prostate and small cell lung cancer so studies have been done to find a reliable inhibitor for LSD1. Monamine oxidases utilize the FAD co-factor much like LSD1 and inhibitors of monamaine oxidase have proven to be successful in inhibiting the activity of LSD1. Thus inhibition of LSD1 opens new pathways for possible treatments for cancers and disorders.

Disease

Relevance

Structural highlights

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.