This is a default text for your page GeorgeAnna/VKOR. 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

Biological Role

(VKOR) is a reducing enzyme composed of 4-helices that spans the endoplasmic reticulum as a transmembrane protein ^[3]. Its enzymatic role is reducing (KO) to Vitamin K Hydroquinone (KH2) ^[4] (Figure 1). The mechanism first occurs through the binding KO and using two cysteine residues to reduce KO into Vitamin K. Then, a second pair of cysteine residues will reduce Vitamin K into the final product, KH2 (Figure 1). One of VKORs primary roles is to assist in blood coagulation through this KH2 regeneration mechanism. With Vitamin K as a cofactor, the γ-carboxylase enzyme will enact post-translational modification on KH2, oxidizing it back to KO. The oxidation of KH2 by γ-carboxylase is coupled with the carboxylation of a glutamate residue to form γ-carboxyglutamate. The coupling of this oxidation and carboxylation will activate several clotting factors in the coagulation cascade.

Author's Notes

Figure 1. Mechanism of KO oxidation into KH2.

Structural Highlights

Structural Overview

VKOR has many key structural components that allow it to maintain proper functionality and catalytic abilities. The VKOR binding pocket provides specific substrate binding via highly conserved residues that recognize the target substrates. The pocket works in conjunction with the cap domain. The cap domain is a helical component of VKOR that facilitates conformational transitions from the to the once a substrate binds. Interactions between the cap domain, binding pocket, and the bound protein are critical to achieve full activation of Vitamin K. Another necessary part of the structure is the anchor. The anchor serves as a way to hold VKOR in the proper orientation within the cell membrane such that all enzymatic components are in the correct proximity for substrate binding and catalysis. Vital to the VKOR structure and these components are two disulfide bridges. The first appears slightly above the binding pocket between C132 and C135. The second occurs within the cap domain between C43 and C51. These cysteines are catalytic residues that also aid in the transition of VKOR from the open conformation to the closed conformation and the reduction of KO.

Active Site

Within the four transmembrane helices lies the . The binding pocket is comprised of a containing , N80 and Y139, that interact with substrates. The hydrophobic pocket provides specificity to the region while the hydrophilic residues hydrogen bond to the substrate, providing recognition and increasing specificity. The above the binding pocket provides stabilization when a substrate is bound. This bridge provides increased stability for the binding site as it interacts with and binds substrates or inhibitors. The hydrophilic residues provide when interacting with substrates for specificity and recognition. Upon binding, VKOR will transition into the closed conformation allowing the catalytic mechanism to commence.

Cap Domain

Anchor

Function: Method of Coagulation

Brief Overview

In its resting state, VKOR is in an , prepared for a substrate to bind. Once the substrate binds, this will induce the closed conformation of VKOR, where the catalytic mechanism will activate Vitamin K via reactive cysteine residues. Vitamin K will then be released from the binding pocket for use in the body, and VKOR will return to the open conformation once again. The enzyme will then reset into its reactive state to prep for another molecule of Vitamin K to bind.

Catalytic Mechanism

The catalytic mechanism of VKOR is a critical part of its overall function in the body. Highly regulated enzymatic activity through the reactivity of catalytic cysteines allows VKOR to properly activate Vitamin K for its use in the body. The enzyme begins in , where it's in the open conformation with the cap domain open to allow in a substrate to bind to the active site. Once a substrate binds, the cap domain is initiated into the closed conformation. VKOR is now in . To further stabilize the closed conformation with the substrate bound, the cap domain helps initiate a catalytic reaction of cysteines to break the disulfide bridge that was stabilizing stage 1. Free cysteines are now available that provide strong stabilization of the closed conformation through interactions with the cap domain and the bound substrate. This puts the enzyme in , where the catalytic free cysteines react to form a new disulfide bridge, releasing the activated substrate into the blood stream to promote anticoagulation. With two stable disulfide bridges and VKOR unbound, the enzyme is now in its final, unreactive . VKOR must undergo conformational changes to return to Stage 1 and restart the catalytic process to activate Vitamin K again.

Disease and Treatment

Afflictions

Inhibition

The most inexpensive and common way to treat blood clotting is through the VKOR inhibitor, . Warfarin is able to do so by outcompeting KO. It will enter the binding pocket of VKOR, creating strong hydrogen bonds with the active site.

Mutations

Some key that can be detrimental to the VKOR structure are mutations of the . The two main residues, N80 and Y139, can be mutated to A80 and F139 creating a decrease in recognition and stabilization.

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.