The Bh3 Domain of Puma: Structure Determination and Small Molecular Inhibitor Design. Nicki Zevola Bahar Lab Lab Meeting March 25, 2009. Intro. What are BCl-2 proteins?. 1. A class of pro-survival and pro-apoptotic proteins Easily distinguishable
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Lab Meeting March 25, 2009
Crystal structure of BCl-xl (mouse)
Crystal structure of Puma (mouse)
Goal of Project: Develop small molecule mitochondrial-targeted drugs to inhibit the binding of the Puma Bh3 domain to Bcl-2 family proteins.
Normally, Puma Bh3 domain:Bcl-2 protein binding antagonizes anti-apoptotic Bcl-2 proteins, inhibiting Apaf-1, and resulting in caspase release and apoptosis.
Studies with Puma-deficient mice have shown that Puma not only activates, but is required for, apoptosis induced by oncogenes and DNA-damaging agents.1,2Project Overview
1Qui et. al. PUMA Regulates Intestinal Progenitor Cell Radiosensitivity and Gastrointestinal Syndrome. Cell Stem Cell. 2008. 2(6):576-583.
2 Yu J., Zhang L., Hwang PM, Kinzler K.W., Vogelstein B. Puma induces the rapid apoptosis of colorectal cancer cells. Mol. Cell.2001. 7:3:673-82.
Analyze structure of Bh3 domain of Puma
Determine key conserved interactions between Puma Bh3 domain and Bcl-2 proteins
Develop pharmacophore models using conserved interactions
Screen Zinc 8.0 database for lead-like compounds that match pharmacophore model
Develop Puma models to prioritize hits
In vitro testing
Step 2. Determine key conserved interactions Structures were Obtained
between Puma Bh3 domain and BCl-2 proteins
Bh3 domains of Noxa (in yellow, left) and Puma (in pink,right).
Images courtesy Gabriela Mustata, Ph.D.
Step 3. Develop pharmacophore models proteins (con’t)
using conserved interactions
Slide courtesy Dr. Gabriela Mustata, Ph.D.
Step 4. Screen Zinc 8.0 database for proteins (con’t)
compounds that match pharmacophore model
Difficulties Encountered Thus Far proteins (con’t)
Questions? Ideas? Comments? proteins (con’t)
A special thank you: Dr. Ivet Bahar; Dr. Gabriela Mustata; Dr. Jian Yu; Dr. Joel Greenberger; Ahmet Bakan (for teaching MD Simulations); everyone else for listening,