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| This Sandbox is Reserved from January 19, 2016, through August 31, 2016 for use for Proteopedia Team Projects by the class Chemistry 423 Biochemistry for Chemists taught by Lynmarie K Thompson at University of Massachusetts Amherst, USA. This reservation includes Sandbox Reserved 425 through Sandbox Reserved 439. |
Contents |
LRRK2/Kinase Inhibitors
Introduction
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This is our scene for depicting protein chains from the N terminus to C terminus using rainbow coloring.
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This scene focuses on the chemical component of 4PY1.
Overall Structure
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Outline of Topics:
- Secondary Structure Elements
- Location and organization
- Polar and Non-polar Groups
- Location and organization
When you look at the , you see that most are polar and fewer are non-polar. Conversely, the consist almost entirely of non-polar groups.
- Identify Hinge Location (Connects Sub-units)
- Identify Cystine Bonded to Ligand
Binding Interactions
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LRRK2 contains binding sites for 6-[(2,5-dimethoxyphenyl)sulfanyl]-3-(1-methyl-1H-pyrazol-4-yl)[1,2,4]triazolo[4,3-b]pyridazine which we will refer to by its PDB code, 2YK.
The residues involved in binding interactions are listed below:
- LEU 903A
- VAL 911A
- GLY 1040A
- GLU 979A
- VAL 981A
These residues are highlighted in green and the ligand 2YK is shown in blue.
The scene below provides an alternative view of the binding interactions with the residues labelled in red with their corresponding number and the ligand, 2YK, labelled in blue.
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Additional Features
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LRRK2 is comprised of multiple domains:
- armadillo repeat (ARM)
- ankyrin repeat (ARK)
- leucine rich repeat (LRR)
- ras complex (ROC)
- C-terminal of ROC (COR)
- kinase
- WD40 repeat.
The most well-known mutation, which occurs in the kinase domain, plays a role in Parkinson’s disease because it increases the kinase activity of LRRK2.
Mutations also occur in the ROC domain and play an indirect role in kinase activity.
Overview of Mechanism/Function
- GTP binding in the ROC domain regulates kinase activity
- Two PD associated residues, R1441 and I1371 , stabilize the ROC dimer
- Mutations cause destabilization at these sites decreasing GTPase activity (and kinase activity)
Quiz Question 1
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There is a hinge structure created by a covalent interaction in the form of a disulfide bond. This is created by the shown here with the ligand. This bond allows several to open and close, allowing the substrate to enter the ROC region. A mutation that replaces the cysteine drastically reduces kinase activity, as it prevents hinge movement. Similarly, a mutation that adds another cysteine bond also reduces kinase activity. Propose an explanation for why kinase activity is reduced in either case. In your explanation include ideas of feedback inhibition, initial velocity and the effect of either mutation on Km and Vmax.
Quiz Question 2
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For our second question I am going to present a green scene with the binding pocket and the ligand shown. The green scene will show the details of the binding pocket including the secondary structures and the residues which make them up. I will then ask the student to think about the scene and give three alternations to the ligand which would make it a better competitive inhibitor.
See Also
- [2ZEJ]
- [Leucine-rich Repeat]
- [Crystal structure of a leucine-rich repeat protein]
- [Leucine-rich repeat-contain protein 4]
- [[1]]
Credits
Introduction - Megan Greiner
Overall Structure - Nick Barberio
Drug Binding Site - John Vetrano
Additional Features - Nicole Garvin
Quiz Question 1 - Charit Tippareddy
Quiz Question 2 - Peter Kelly
