University of Arkansas Center for Protein Structure and Function Receives $10.2 million from NIH

FAYETTEVILLE, Ark. — The University of Arkansas Center for Protein Structure and Function has received a $10.2 million award from The National Institutes of Health National Center for Research Resources. This new five-year grant, the largest competitive research grant ever received by the University of Arkansas, will provide funding to continue the center, which was established in October 2000 with a $9.6 million NIH grant.

This grant was written by faculty members in the departments of chemistry and biochemistry, and biological sciences on the Fayetteville campus, and the department of biochemistry and molecular biology at the University of Arkansas for Medical Sciences. Frank Millett is the principal investigator of the grant, and Roger Koeppe II is the co-principal investigator. Millett is a Distinguished Professor and Koeppe is a University Professor in the J. William Fulbright College of Arts and Sciences.

“The receipt of this outstanding grant attests to the excellent research work in progress by University of Arkansas faculty,” said Collis Geren, dean of the graduate school and vice provost for research.  “Funding from public agencies is critical to advancing research projects and supporting centers and provides an attractive incentive when recruiting students and faculty. We’re looking forward to watching the progress of the Center for Protein Structure and Function’s work as it serves Arkansas and the world.”

About Centers of Biological Research Excellence

Proteins do nearly all the work in the cells of our bodies, ranging from brain function and nerve transmission to metabolic energy production and muscular contraction. Moreover, most diseases are associated with defects in protein function. Future advances in the diagnosis and treatment of human disease will depend upon better understanding of the thousands of proteins that are encoded within the genomes of humans and human pathogens. The University of Arkansas Center for Protein Structure and Function, one of many Centers of Biological Research Excellence around the nation, seeks to contribute to this fundamental understanding through detailed investigations of the molecular structure and function of proteins that play an important role in human disease.   

More than 20 faculty members and 30 graduate students, postdoctoral students and technical staff work as multidisciplinary teams in the center to develop innovative approaches to biomedical research in protein structure and function. David Vicic, Matt McIntosh, and Bob Gawley will develop new synthetic methods to prepare compounds that block chemokine receptors to provide a potential treatment for HIV infection. Robyn Goforth, Suresh Kumar, and Ralph Henry will study the protein targeting process which sends a protein to its correct location in the cell. Joshua Sakon, Kathryn Curtin and Michael Lehmann are studying protein interactions in the extracellular matrix, with the goal of developing a novel drug delivery system.  Denise Greathouse, Grover P. Miller, and Roger Koeppe II will carry out a project on the structure and function of membrane proteins, which play a crucial role in nerve transmission in brain and muscle. Suresh Kumar and Joshua Sakon will study the fibroblast growth factor signaling complex, which plays a key role in cell growth and wound healing. Millett and Bill Durham will develop a new laser-excitation method to study how electron transfer in the mitochondria is used to produce all the energy needed by the biological cell.       

The new grant will allow the university to bring in four new faculty members to the Fayetteville campus, and one to UAMS.  The U of A has provided matching funds that played an important role in securing the NIH grant. In addition to supporting the new faculty positions, the university will complete the $17 million renovation of the chemistry building, which was initiated with an NIH NCRR grant written by COBRE investigator Wesley Stites. The center will also expand state-of-the-art core facilities in NMR spectroscopy, X-ray crystallography, mass spectrometry, and high-throughput drug design and synthesis.   

Multidisciplinary Research Projects in the Center

Drug Discovery and Design: David Vicic will direct a project to develop new synthetic methods to prepare compounds that block chemokine receptors to provide a potential treatment for HIV and AIDS.  HIV uses the chemokine receptors to insert itself into the target cell membrane and initiate HIV infection.  The Vicic Lab has recently developed new methods to form carbon-carbon bonds under mild conditions, which promise to greatly expedite the synthesis of a large pool of potential chemokine antagonists.

Protein Targeting: Robyn Goforth, Suresh Kumar, and Ralph Henry will carry out a project on the role of signal recognition particles (SRP), which are components of an elaborate protein targeting system that delivers newly synthesized proteins to transporters present in the endoplasmic reticulum, a network of membranes in cells. Malfunction of the protein targeting system in humans is implicated in idiopathic inflammatory myopathies, diabetes mellitus, and colon cancer. Goforth and her colleagues are using NMR and other techniques to develop a structure-based understanding of the protein targeting mechanism.  

Protein Interactions with the Extracellular Matrix:   Joshua Sakon, Kathryn Curtin and Michael Lehmann are studying protein interactions in the extrcellular matrix. Sakon is developing a novel drug delivery system based on the interaction of a collagen-binding domain protein (CBD) with collagen in the extracellular matrix. He has recently determined the X-ray crystal structure of a CBD protein to high resolution, and is studying the interaction of CBD with collagen. Fusion of the CBD with autocrine/paracrine peptide signaling molecules should provide a promising new approach to deliver the drug to the extracellular matrix for optimal effect. 

State-of-the-art Core Facilities

Nuclear Magnetic Resonance Spectroscopy Core Facility

James Hinton and Suresh Kumar have established a new state-of-the-art core facility in protein Nuclear Magnetic Resonance spectroscopy, which is used to determine the complete three-dimensional structures of proteins. The new facility includes a 700 MHz NMR with a cryoprobe, which is the first to be installed in the United States, and offers significant advantages for the study of large proteins.

Protein X-ray Crystallography Core Facility

Joshua Sakon and Wesley Stites have established an X-ray crystallography core facility that includes two Rigaku diffractometers and robotic protein crystallization instruments.  Many investigators in the center are collaborating with Sakon to determine the complete three-dimensional structures of proteins using X-ray crystallography. 

The Mass Spectrometry core facility is directed by Jackson Lay, Charles Wilkins, and Kevin Raney.  Charles Wilkins is a pioneer in the development of Fourier transform mass spectrometry.  The mass spectrometry core facility will include a broad array of modern mass spectrometers, including an IonSpec 9.4 Tesla Fourier transform mass spectrometer equipped with MALDI and ESI sources.  The availability of these state-of-the-art mass spectrometers gives the center unique resources for characterizing protein structure and function. 

High-Throughput Synthesis Core Facility

Robert Gawley and Matt McIntosh have established a High-Throughput Synthesis Core Facility.  A significant effort is being made in the center to study the interactions of small organic molecules with proteins, which is the basis for the action of most pharmaceuticals. State-of-the-art instrumentation and expertise is available in the core facility for the diversity-oriented synthesis of libraries of small molecules to be used to probe protein structure and function, and for drug discovery.