Visualizing AngiogenesisA CREST Initiative

Elise A. Pellmann – Marquette UniversityDaniel Sem, Ph.D. – Concordia University WisconsinDavid Goodsell, Ph.D. – Scripps Research Institute

2. Movie1. Cellular landscape

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

C

N

catalytic domain

ERK-binding domain

++

––

•C: PDB 2G6Z

•N: Homology model, NMR

•Linker: hand-drawn

•Domain orientation: good guess?

DUSP-5 model

C

N

catalytic domain

ERK-binding domain

++

––

1.ERK binding

2.catalytic domain “clamps” down

3.phosphates removed from ERK

Drug impedes catalytic action, may also prevent ERK binding if DUSP-5 clamps down on drug

• Daniel Sem, Terrence Neumann, Prachi Pradeep

• David Goodsell

• Margaret Franzen, MSOE

• CREST grant

Movie viewing

Thank you