C P F MC P F M

Chemical Chemical Proteomics Proteomics

Facility at Facility at MarquetteMarquette

The post-genomic challenge Exploring function across protein families using chemical probes

The CPFM is in early stages of development Projects focus on studies of protein function (applied genomics) Participants from:

- MCW- Marquette (Biology & Chemistry)- UW-Milwaukee (MFBSC)- UW-Madison (NMRFAM)

Long term goal: “Science in Service to Society”

Internet2: Enabling Post-Genomic Technology at Marquette

Applied research

Basicresearch

Internet2: Turning the CPFM into a Collaboratorium

Potential Benefits:

- Better understanding of biology - Pharmacogenomics & personalized medicine- Treatments for currently untreatable disease- Drugs with fewer side effects - Better understanding of toxicology of pollutants

The Promise of Genomics: not yet realized …

“The human genome is data not knowledge, and will be useless until we understand what it means.” attributed to Sydney Brenner

Genes => Proteins

C P F MC P F M

Chemical Chemical Proteomics Proteomics

Facility at Facility at MarquetteMarquette

The post-genomic challenge Exploring function across protein families using chemical probes

What is the Chemical Proteomics Facility at Marquette?Resources (equipment, software) and people

With a mission to: Enable Chemical Proteomic studies of protein-ligand interactions Facilitate collaboration across departments and institutions Provide a better understanding of basic biology Use science to address social needs Train scientists and entrepreneurs with social conscience

S3 = Biotechnology with social conscience: science, business, law and engineering

Beowulf/Linux cluster facility Modelling lab: remote access to NMRFAM

NMR spectrometer lab Fluorescence assay lab

CPFM Resources at Marquette:

Equipment

C P F MC P F M

Chemical Chemical Proteomics Proteomics

Facility at Facility at MarquetteMarquette

The post-genomic challenge Exploring function across protein families using chemical probes

Internet2: The CPFM as a Collaboratorium

Chemistry Biology

I2 I2

I2

1) Need High Speed (I2) Connection to MFBSC

Viewing of microscopy results at CPFM (imaging)

CPFM Client

I2

Fluorescence imaging as a window to:a) Zebrafish developmental biologyb) Drug transport

Zebrafish Estrogen Receptors (endocrine disruptor targets)

Computationally derived with homology modeling

Estrogen receptor… is a protein targeted by endocrinedisruptor pollutants (EPA regulations)

2) Need High Speed (I2) Connection to NMRFAM

CPFM Client

I2I2

Milo Westler, Ph.D.Operations Director

NMRFAM

Teleconference to NMRFAM: what is NMRFAM?

Computational Docking for Drug Design

(Dock, Autodock, Caveat & Grid)

HIV Protease inhibitor

Can use protein structure to design better drugs

And to avoid drug metabolism:-Toxic side effects-Drug/drug interactions

University of Texas at Austin

National Partnership for Advanced Computational Infrastructure

IBM Power 4 system

3) Need High Speed (I2) Connection to UTA

Marquette’s Beowulf cluster

CPFM Client

- Ligand-protein docking- Homology modeling- Chemoinformatic analysis of drug properties

I2I2

Fragments

1

N

N

2

N

N

O3

O

4

N

N5

7

S

N

6

8

N

9

N+

N

10

O-

O

N

11

N

N O

O

O

12

Molecular Legos?

Unique enabling of Chemoinformatics at Marquette

Summary

C P F MC P F M

Chemical Chemical Proteomics Proteomics

Facility at Facility at MarquetteMarquette

The post-genomic challenge Exploring function across protein families using chemical probes

Internet2: Enabling remote access & collaboration

NMRFAM and MFBSC facilities Computational resources (UT-Austin; Marquette) Access to local computational data & tools (chemoinformatics)

Databases: endocrine disruptors; optimized drug building blocks

S3: better drugs, better pollutant screening, basic Biology

Current CPFM Projects and Participants

Medical College of Wisconsin- Henry Miziorko: Enzymes in the mevalonate biosynthetic pathway: structural and mechanistic studies - Jung-Ja Kim: Structural characterization of molecular motion in NADPH-cytochrome P450 oxidoreducatase

Marquette: Chemistry- James Kincaid: Complementary use of NMR & Raman studies to probe substrate binding to cytochrome P450 - Dan Sem: Probing protein-ligand interactions in toxicology and chemical proteomics: methods and application

Marquette: Biology- Pinfen Yang: Mechanism of flagellar radial spoke: ligand binding and structural studies of radial spoke protein 2

- Rosemary Stuart: Role of Su e in oligomerizing the F1-F0 ATP synthase complex: structural and binding studies

Other collaborators and resources: UW-Milwaukee: Marine and Freshwater Biomedical Sciences Center UW-Madison: NMR Facility UT-Austin: Supercomputer Facility (NSF)