Download Visualizing Angiogenesis

Visualizing Angiogenesis
A CREST Initiative
Elise A. Pellmann – Marquette University
Daniel Sem, Ph.D. – Concordia University Wisconsin
David Goodsell, Ph.D. – Scripps Research Institute
1. Cellular landscape
2. Movie
1. Cellular landscape
• 2 x 107 magnification
• Show:
• MAPK and receptor tyrosine kinase signaling
• VEGF, plurality of biochemical cascades
• angiogenesis
• cell permeability
Knowledge needed for landscape
• pathway: which proteins?
• size, domain arrangement/shape,
assembly, modifications,
interactions/function
Pathway: KEGG
Pathway
Proteins (i)
Proteins (ii)
Sketches
Final version
2. Movie
• PyMOL, 3D
• Show: drug binding to DUSP-5
DUSP-5
• ERK-2 phosphatase: P-T183, P-Y185
• C-terminal phosphatase domain
• N-terminal ERK-binding domain
• linker region
• Ser to Pro mutation (hemangiomas)
DUSP-5 model
N
+
+
–
–
C
catalytic domain
•C: PDB 2G6Z
•N: Homology
model, NMR
•Linker: handERK-binding domain drawn
•Domain
orientation: good
guess?
DUSP-5 model
1.ERK binding
N
+
+
–
–
C
catalytic domain
2.catalytic domain
“clamps” down
3.phosphates removed
from ERK
ERK-binding domain Drug impedes catalytic
action, may also
prevent ERK binding if
DUSP-5 clamps down
on drug
Movie viewing
Thank you
• Daniel Sem, Terrence Neumann, Prachi Pradeep
• David Goodsell
• Margaret Franzen, MSOE
• CREST grant