'Missing Link' May Spur New Brain Disorder Drugs

VANDERBILT V UNI VE RS I TY MEDICAL CENTER www.mc.vanderbilt.edu/reporter Friday, March 14, 2014 VUMC Weekly Publication 'Missing link' may spur new brain disorder drugs by Bill Snyder the class C subfamily of G protein-cou tal structure of the receptor's "trans postdoctoral fellow Karen Gregory, Researchers at the Scripps Research pled receptors (GPCRs) through which membrane domain" bound to a "nega Ph.D.; drug discovery scientist Institute in San Diego and Vanderbilt hormones, neurotransmitters and more tive allosteric modulator" or NAM. The Hyekyung Cho, Ph.D.; and graduate stu University have discovered a "missing (rum a third of all thera~utic drugs exert compound "tunes down" the receptor dent Yan Xia. link" in the structure of a transmem their effects. when activated by glutamate like the "This work leveraged the unique brane receptor that could lead to new "This receptor family is an exciting dimmer switch of an electrical circuit. strengths of the Vanderbilt and Scripps treatments for autism, schizophrenia, new target for future medicines for treat The Scripps team included first teams in applying structural biology, Parkinson's disease and Alzheimer's dis ment of brain disorders," said P. Jeffrey author Huixian Wu and Chong Wang, molecular modeling, allosteric modula ease. Conn, Ph.D., director of the Vanderbilt both graduate students, staff scientist tor pharmacology and structure activity In an article posted online last week in Center for Neuroscience Drug Discovery Gye Won Han, Ph.D., assistant professor relationships to validate the receptor Science magazine, the researchers, led by (VCNDD), who contributed to the study. Vsevolod Katritch, Ph.D., and associate structure," Niswender said. senior author Raymond Stevens, Ph.D., "This new understanding of how professor Vadim Cherezov, Ph.D. National Institutes of Health grants professor of Molecular Biology and drug-like molecules engage the receptor The Vanderbilt team included Colleen that supported the research included Chemistry at Scripps, achieved the first at an atomic level promises to have a Niswender, Ph.D., VCNDD director of GM094618, GM073197, NS031373, high-resolution crystal structure of a major impact on new drug discovery Molecular Pharmacology and research NS078262 and MH090192; additional metabotropic glutamate receptor, mGlul. efforts," said Conn, the Lee E. Limbird associate professor of Pharmacology; support was provided by the The receptor, which binds the neuro Professor of Pharmacology. Jens Meiler, Ph.D., associate professor of International Rett Syndrome transmitter glutamate, is a member of The researchers determined the crys- Chemistry and Pharmacology; former Foundation.O Health inforrrtatics • • The team study services reorganizes ing beta-cell regeneration includes, from to rrteet users' needs left, Chunhua Dai,M.D., by Paul Govern Informatics Officer. Support for Medical Center On March 5 in 208 Light Kristie Aamodt, operations is now named Ha 11 . Middleton announcPCI Marcela .

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Alberto Cisneros, Amanda M. Duran, Jessica A. Finn, Darwin
This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. Current Topic pubs.acs.org/biochemistry Protocols for Molecular Modeling with Rosetta3 and RosettaScripts † ‡ ‡ § ‡ ∥ ‡ ⊥ ‡ ∥ Brian J. Bender, , Alberto Cisneros, III, , Amanda M. Duran, , Jessica A. Finn, , Darwin Fu, , ‡ # ‡ ∥ ‡ ∥ ‡ § Alyssa D. Lokits, , Benjamin K. Mueller, , Amandeep K. Sangha, , Marion F. Sauer, , ‡ § ‡ ∥ ‡ † ‡ § ∥ ⊥ # Alexander M. Sevy, , Gregory Sliwoski, , Jonathan H. Sheehan, Frank DiMaio,@ Jens Meiler, , , , , , ‡ ∥ and Rocco Moretti*, , † Department of Pharmacology, Vanderbilt University, Nashville, Tennessee 37232-6600, United States ‡ Center for Structural Biology, Vanderbilt University, Nashville, Tennessee 37240-7917, United States § Chemical and Physical Biology Program, Vanderbilt University, Nashville, Tennessee 37232-0301, United States ∥ Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States ⊥ Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee 37232-2561, United States # Neuroscience Program, Vanderbilt University, Nashville, Tennessee 37235, United States @Department of Biochemistry, University of Washington, Seattle, Washington 98195, United States *S Supporting Information ABSTRACT: Previously, we published an article providing an overview of the Rosetta suite of biomacromolecular modeling software and a series of step-by-step tutorials [Kaufmann, K. W., et al. (2010) Biochemistry 49, 2987−2998]. The overwhelming positive response to this publication we received motivates us to here share the next iteration of these tutorials that feature de novo folding, comparative modeling, loop construction, protein docking, small molecule docking, and protein design. This updated and expanded set of tutorials is needed, as since 2010 Rosetta has been fully redesigned into an object-oriented protein modeling program Rosetta3.
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1 Jonathan H. Sheehan, Ph.D. Director, Program in Personalized Structural Biology / Precision Medicine Research Associate Professor Phone (W): 615-936-2516 Center for Structural Biology and Dept. of Biochemistry Phone (H): 615-673-9457 Vanderbilt University PMB 407917 Fax: 615-936-2211 5137 BIOSCI/MRB III [email protected] 465 21st Ave. South http://structbio.vanderbilt.edu/~sheehajh/ Nashville, TN 37232-8725 DOB: 1/29/1966, New Haven, CT Education 1984 - 1988 Harvard College (Cambridge, MA), A.B. with honors, Classics Summer 1987 Aegean Institute (Galatas, Greece) with honors in Greek and classical drama 2000 - 2006 Ph.D. Biochemistry, Vanderbilt University. Mentor: Walter Chazin Dissertation Title: Probing functional diversity of EF-hand calcium-binding proteins through mutant design and structural analysis 2006 - 2008 Postdoctoral Training: Vanderbilt University. Mentor: Jens Meiler Academic Appointments 1990 - 1995 Research Asst. in Jim Forman©s lab, Immunology at UTSW Med. Ctr., Dallas, TX 1995 - 1996 Research Asst. in the Embryonic Stem Cell Core Lab at VUMC 1996 - 1997 Research Asst. in Mark Magnuson©s lab, Molecular Physiol. and Biophys., VUMC 1997 - 2000 Manager of Dave Piston©s Cell Imaging Core Lab at VUMC 2009 - 2011 Research Instructor, Dept. of Biochemistry and V.U. Center for Structural Biology 2011 - 2016 Research Assistant Professor, Dept. of Biochemistry and Ctr. for Structural Biology 2016 - present Research Associate Professor, Dept. of Biochemistry and Ctr. for Structural Biology 2016 - present Program Director in Personalized Structural Biology / Precision Medicine Employment (other than academic appointments) 1989 - 1990 Peace Corps Volunteer, building potable water systems in Cañar, Ecuador Teaching June 2007 Vanderbilt University Center for Structural Biology Workshop: Molecular Visualization Tools and Analysis (with Eric Dawson) Aug.
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Bild Der Wissenschaft 2010, 4, 18-23
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