研究领域

Biochemistry/Physical Chemistry

Our research interests focus on the roles of membrane proteins in human health and disease, with a particular interest in membrane proteins with therapeutic potential. Membrane proteins, as a class, make up the majority of therapeutic targets and play essential roles in biology and pathophysiology. We investigate the structure, dynamics, and function of this class of proteins with an interdisciplinary approach synthesizing the output from multiple disparate techniques which allows us to tackle challenging yet biomedically relevant problems. Our investigations focus on the following three themes: 1) TRP channel gating and modulation. TRPM8 functions as the primary cold sensor in humans where it integrates, thermo-, chemical-, and voltage-dependencies and is modulated by other proteins and lipids. This channel has significant therapeutic potential in diverse and important diseases such as cancer, chronic pain, obesity, and diabetes. We seek to understand the mechanism of how TRPM8 integrates distinct stimuli and modulators in an effort to unlock the therapeutic potential of TRPM8. 2) Membrane protein structural enzymology. Our lab focuses on two membrane enzymes; vitamin K epoxide reductase (VKOR) and undecaprenol kinase (UDPK). VKOR is the target of the popular anticoagulant warfarin (also Coumadin?) and is one of the hallmark targets of personalized medicine. Undecaprenol kinase is a known virulence factor in gram-positive bacteria and an excellent target for narrow spectrum antibiotic development. For these enzymes we seek to understand the relationship between structure, function, and dynamics. 3) Methods Development for membrane protein structural biology. In an effort to push the boundaries of membrane protein structural biology, we are exploring the use of new, and fine-tuning existing membrane mimics that are compatible with solution NMR. Of particular interest is optimizing reverse micelles as hosts for membrane proteins which have the particular advantage of significantly increasing the size and complexity of NMR-accessible membrane targets. To accomplish these goals, our research program relies on a number of interdisciplinary techniques including nuclear magnetic resonance spectroscopy (NMR), electrophysiology, enzymology, and computational structural biology.

近期论文

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Van Horn WD. VKORC1 ER mislocalization causes rare disease. Blood. 2014 Aug 21;124(8):1215-16. doi: 10.1182/blood-2014-07-586032. PubMed PMID: 25147380; PubMed Central PMCID: PMC4141510 Peng D, Kim JH, Kroncke BM, Law CL, Xia Y, Droege KD, Van Horn WD, Vanoye CG, Sanders CR. Purification and Structural Study of the Voltage-Sensor Domain of the Human KCNQ1 Potassium Ion Channel. Biochemistry. 2014 Apr 1;53(12):2032-42. doi:10.1021/bi500102w. PubMed PMID: 24606221; PubMed Central PMCID: PMC3977583. Van Horn WD. Structural and functional insights into human vitamin K epoxide reductase and vitamin K epoxide reductase-like 1. Crit. Rev. Biochem. Mol. Biol. 2013. Jul-Aug;48(4):357-72. doi:10.3109/10409238.2013.791659. Epub 2013 Apr 30. Barrett PJ, Chen J, Cho MK, Kim JH, Lu Z, Mathew S, Peng D, Song Y, Van Horn WD, Zhuang T, Sönnichsen FD, Sanders CR. The quiet renaissance of protein nuclear magnetic resonance. Biochemistry. 2013 Feb 26;52(8):1303-20. doi: 10.1021/bi4000436. Epub 2013 Feb 12. PubMed PMID: 23368985; PubMed Central PMCID: PMC3592982. Shi M, Pedchenko V, Greer BH, Van Horn WD., Santoro SA, Sanders CR, Hudson BG, Eichman BF, Zent R, Pozzi A. Enhancing integrin α1 inserted (I) domain affinity to ligand potentiates integrin α1β1-mediated down-regulation of collagen synthesis. J Biol Chem. 2012 Oct 12;287(42):35139-52. doi: 10.1074/jbc.M112.358648. Epub 2012 Aug 10. PubMed PMID: 22888006; PubMed Central PMCID: PMC3471707. Barrett PJ, Song Y, Van Horn WD, Hustedt EJ, Schafer JM, Hadziselimovic A, Beel AJ, Sanders CR. The amyloid precursor protein has a flexible transmembrane domain and binds cholesterol. Science. 2012 Jun 1;336(6085):1168-71. doi: 10.1126/science.1219988. PubMed PMID: 22654059; PubMed Central PMCID: PMC3528355. Lu Z, Van Horn WD, Chen J, Mathew S, Zent R, Sanders CR. Bicelles at low concentrations. Mol Pharm. 2012 Apr 2;9(4):752-61. doi: 10.1021/mp2004687. Epub 2012 Jan 20. PubMed PMID: 22221179; PubMed Central PMCID: PMC3319193. Van Horn WD, Sanders CR. Prokaryotic diacylglycerol kinase and undecaprenol kinase. Annu Rev Biophys. 2012;41:81-101. doi: 10.1146/annurev-biophys-050511-102330. Epub 2011 Dec 20. PubMed PMID: 22224599. Van Horn WD, Vanoye CG, Sanders CR. Working model for the structural basis for KCNE1 modulation of the KCNQ1 potassium channel. Curr Opin Struct Biol. 2011 Apr;21(2):283-91. doi: 10.1016/j.sbi.2011.01.001. Epub 2011 Feb 4. Review. PubMed PMID: 21296569; PubMed Central PMCID: PMC3070781. Kang C, Vanoye CG, Welch RC, Van Horn WD, Sanders CR. Functional delivery of a membrane protein into oocyte membranes using bicelles. Biochemistry. 2010 Feb 2;49(4):653-5. doi: 10.1021/bi902155t. PubMed PMID: 20044833; PubMed Central PMCID: PMC2811756. Van Horn WD, Beel AJ, Kang C, Sanders CR. The impact of window functions on NMR-based paramagnetic relaxation enhancement measurements in membrane proteins. Biochim Biophys Acta. 2010 Feb;1798(2):140-9. doi: 10.1016/j.bbamem.2009.08.022. Epub 2009 Sep 12. PubMed PMID: 19751702; PubMed Central PMCID: PMC2812639. Kim HJ, Howell SC, Van Horn WD, Jeon YH, Sanders CR. Recent Advances in the Application of Solution NMR Spectroscopy to Multi-Span Integral Membrane Proteins. Prog Nucl Magn Reson Spectrosc. 2009 Nov 1;55(4):335-360. PubMed PMID: 20161395; PubMed Central PMCID: PMC2782866. Van Horn WD, Kim HJ, Ellis CD, Hadziselimovic A, Sulistijo ES, Karra MD, Tian C, Sönnichsen FD, Sanders CR. Solution nuclear magnetic resonance structure of membrane-integral diacylglycerol kinase. Science. 2009 Jun 26;324(5935):1726-9. doi: 10.1126/science.1171716. PubMed PMID: 19556511; PubMed Central PMCID: PMC2764269. Van Horn WD, Ogilvie ME, Flynn PF. Reverse micelle encapsulation as a model for intracellular crowding. J Am Chem Soc. 2009 Jun 17;131(23):8030-9. doi: 10.1021/ja901871n. PubMed PMID: 19469539. Van Horn WD, Ogilvie ME, Flynn PF. Use of reverse micelles in membrane protein structural biology. J Biomol NMR. 2008 Mar;40(3):203-11. doi: 10.1007/s10858-008-9227-5. Epub 2008 Feb 23. PubMed PMID: 18297402. Flynn PF, Simorellis AK; Van Horn W D. NMR Studies of encapsulated proteins. Annu. Reports NMR Spectroscopy. 2007; 62:179-219. doi: 10.1016/S0066-4103(07)62004-3. Simorellis AK, Van Horn WD, Flynn PF. Dynamics of low temperature induced water shedding from AOT reverse micelles. J Am Chem Soc. 2006 Apr 19;128(15):5082-90. PubMed PMID: 16608342. Van Horn WD, Simorellis AK, Flynn PF. Low-temperature studies of encapsulated proteins. J Am Chem Soc. 2005 Oct 5;127(39):13553-60. PubMed PMID: 16190719.