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Paul
A. Liebman, M.D.
Department of Biochemistry & Biophysics
School of Medicine
143 Anatomy-Chemistry Building/6058
(215) 898-6917 Fax: (215) 898-4217
email: liebmanp@mail.med.upenn.edu
Click here for selected publications since Dr. Liebman's arrival at Penn
RESEARCH INTERESTS
Cellular signaling. Molecular mechanics of G protein activity control in
eye, brain and somatic organs. 7-helix receptor activation and phosphorylation
mechanisms. Protein folding stability. Approaches are designed to carry
analysis of global physiologic behavior ever deeper to the ultimate intramolecular
causes of time course, amplitude and intramolecular recognition control
of essential life processes. RESEARCH TECHNIQUES
Protein molecular structure and function based on physical techniques, including intrinsic tryptophan fluorescence, fluorescence resonance energy transfer (FRET), circular dichroism, UV-VIS absorption spectroscopy, microcalorimetry, computation of molecular dynamics, kinetics, thermodynamics. Protein overexpression and purification, electronic instrumentation.RESEARCH SUMMARY
Events ranging from ion channel flux to gene expression serve brain signaling time scales from seconds to decades. Catalytic activation of many G proteins by a few activated receptors is essential to hormone and neurotransmitter signaling speed and to signal propagation in large cells. It is perhaps for this reason that receptor catalysis mediates a non-covalent, spontaneous tendency of G proteins to become activated by reciprocal ligand exchange of GDP (inactive state) for GTP (active state). These nucleotides are bound with Mg in a cleft between 2 clamshell-like domains of the G protein. The role of active receptor is probably to control the opening rate of this cleft. Spontaneous opening (thermally activated protein breathing and refolding) also occurs, producing physiologic background activity (and noise?) in the absence of receptor activity. GTP binding causes refolding of protein surface moeities that permit controlled recogition and activation of downstream target proteins called effectors. We seek to understand what aspects of the known protein crystal structure
are responsible for determining G protein stability and activation characteristics.
We record the unique, local environment-sensitive properties of protein
tryptophan fluorescence to analyse internal rearrangement dynamics in
G proteins upon activation. We use microcalorimetry to determine the origins
of stability and strengths of ligand-protein interaction. The mechanism
of general anesthetic action is also being studied at these important
neural signaling sites. Receptor-G protein interaction and the role of
receptor phosphorylation and binding of blocking proteins on signal response
termination and down-regulation is also being examined in reconstituted
native membrane systems by these and other spectroscopic and biochemical
methods. Computer modeling of specific reaction mechanisms too complex
for analytic solution allows us to test specific ideas against the data.
