Kottayil I. Varughese, Ph.D.

Professor
Ph.D., University of Madras, India
Office: (501) 686-7160
Lab: (501) 686-7159
KIVarughese@uams.edu

 

My laboratory focuses on the structure elucidation of protein molecules using crystallographic techniques. Additionally, we employ structure-based computational techniques to identify inhibitors for drug targets.

The main areas of interest are: (i) structure of bone proteins relevant to osteoporosis, (ii) platelet glycoprotein interactions in hemostasis and thrombosis, (iii) designing therapeutic inhibitors for LOX-1, a receptor for oxidized LDL, (iv) interactions of methamphetamine and its metabolites with a therapeutic antibody, and (v) structures of proteins involved in bacterial cell wall synthesis.

Structural similarities between human platelet glycoprotein IbαN (green) and variable lymphocyte receptors (VLR) structures from sea lamprey and hagfish (magenta). In ‘Structural origins of hemostasis and adaptive immunity’. J. Ware and K.I. Varughese

Structural similarities between human platelet glycoprotein IbαN (green) and variable lymphocyte receptors (VLR) structures from sea lamprey and hagfish (magenta). In ‘Structural origins of hemostasis and adaptive immunity’. J. Ware and K.I. Varughese

Journal cover art

Affinity improvement of a therapeutic antibody to methamphetamine and amphetamine through structure-based antibody engineering. (a) The binding interactions of the wild-type antibody (b) Interactions of the S93T mutant.

Affinity improvement of a therapeutic antibody to methamphetamine and amphetamine through structure-based antibody engineering. (a) The binding interactions of the wild-type antibody; (b) Interactions of the S93T mutant.

Structure-based Drug Design Targeted at LOX-1, a Receptor for Oxidized Low-Density Lipoprotein

Structure-based Drug Design Targeted at LOX-1, a Receptor for Oxidized Low-Density Lipoprotein


Representative Publications

Ware J, Varughese KI. Structural origins of hemostasis and adaptive immunity. Res Pract Thromb Haemost. 2017;00:1–5. https://doi.org/10.1002/rth2.12045

Pothineni NVK, Karathanasis SK, Ding Z, Arulandu A, Varughese KI, Mehta JL.  LOX-1 in Atherosclerosis and Myocardial Ischemia: Biology, Genetics, and Modulation.  J Am Coll Cardiol. 2017 Jun 6;69(22):2759-2768. doi: 10.1016/j.jacc.2017.04.010. Review.

Ye S, Fujiwara T, Zhou J, Varughese KI, Zhao H.  LIS1 Regulates Osteoclastogenesis through Modulation of M-SCF and RANKL Signaling Pathways and CDC42.  Int J Biol Sci. 2016 25;12(12):1488-1499. 2016.

Fujiwara T, Ye S, Castro-Gomes T, Winchell CG, Andrews NW, Voth DE, Varughese KI, Mackintosh SG, Feng Y, Pavlos N, Nakamura T, Manolagas SC, Zhao H.  PLEKHM1/DEF8/RAB7 complex regulates lysosome positioning and bone homeostasis.  JCI Insight. 2016 Oct 20;1(17):e86330.

Zybailov B, Gokulan K, Wiese J, Ramanagoudr-Bhojappa R, Byrd AK, Glazko G, Jaiswal M, Mackintosh S, Varughese KI, Raney KD.  Analysis of Protein-protein Interaction Interface between Yeast Mitochondrial Proteins Rim1 and Pif1 Using Chemical Cross-linking Mass Spectrometry.  J Proteomics Bioinform. 2015 Nov;8(11):243-252. Epub 2015 Nov 19.

Thakkar S, Wang X, Khaidakov M, Dai Y, Gokulan K, Mehta JL, Varughese KI.  Structure-based Design Targeted at LOX-1, a Receptor for Oxidized Low-Density Lipoprotein.  Sci Rep. 2015 Nov 18;5:16740. doi: 10.1038/srep16740.

Ding Z, Liu S, Wang X, Deng X, Fan Y, Shahanawaz J, Shmookler Reis RJ, Varughese KI, Sawamura T, Mehta JL.  Cross-talk between LOX-1 and PCSK9 in vascular tissues.  Cardiovascular research. 2015; 107(4):556-67. PubMed [journal] PMID:  26092101

Thakkar S, Nanaware-Kharade N, Celikel R, Peterson EC, Varughese KIAffinity improvement of a therapeutic antibody to methamphetamine and amphetamine through structure-based antibody engineering.  Sci Rep. 2014 Jan 14;4:3673. doi: 10.1038/srep03673.

Peterson EC, Celikel R, Gokulan K, Varughese KIStructural characterization of a therapeutic anti-methamphetamine antibody fragment: oligomerization and binding of active metabolites.  PLoS One. 2013 Dec 5;8(12):e82690. doi: 10.1371/journal.pone.0082690. eCollection 2013.

Celikel R., Veldore V.H., Mathews I., Devine K.M., Varughese K.I.  ATP Forms a Stable Complex with the Essential Histidine Kinase WalK (YycG) Domain.  Acta Crystallographica D68, 839-45, 2012

Zarpellon A, Celikel R, Roberts JR, McClintock RA, Mendolicchio GL, Moore KL, Jing H, Varughese K.I., Ruggeri ZM. Binding of a-thrombin to surface-anchored platelet glycoprotein Iba sulfotyrosines through a two-site mechanism involving exosite I.  Proc Natl Acad Sci U S A. 108: 8628-33, 2011.  

Zhao H., Violov A., Veldore V. H., Hoch J. A. and Varughese K. I.  Crystal structure of the transcriptional repressor PagR of Bacillus anthracis.  Microbiology 156: 385-391, 2010

Jende I, Varughese KI, Devine KM.  Amino acid identity at one position within the alpha1 helix of both the histidine kinase and the response regulator of the WalRK and PhoPR two-component systems plays a crucial role in the specificity of phosphotransfer.  Microbiology. 2010 Jun;156(Pt 6):1848-59. doi: 10.1099/mic.0.037515-0. Epub 2010 Feb 18.

Celikel R., Peterson EC, Owens S.M., Varughese K.I.  Crystal structures of a therapeutic single chain antibody in complex with two drugs of abuse-Methamphetamine and 3,4-methylenedioxymethamphetamine.  Protein Science 18 : 2336-45, 2009

Varughese K.I., Zhao H., Veldore, V. H. and Zapf J.  Sporulation phosphorelay proteins and their complexes: Crystallographic characterization.  Methods in Enzymology: 2007 Volume 422: 102-122

Celikel, R., McClintock, R. A., Roberts, J. R, Mendolicchio, G. L., Ware, J., Varughese, K. I., and Ruggeri. Z. M.,  Modulation of α-thrombin function by distinct interactions with platelet glycoprotein Ibα.  Science 2003 301: 218-221.

Celikel, R., Ruggeri, Z.M., and Varughese, K.I.  Modulation of von Willebrand factor conformation and adhesive function by an internalized water molecule.  Nature Structural Biology 2000 7: 881-884.

Link to Dr. KI Varughese at PubMed