John J. Alvarado, PhD
Research Assistant Professor
533 Bridgeside Point II
450 Technology Dr
Education
PhD in Structural Biology, Purdue University, 2003
BA in Chemistry, Our Lady of the Lake University, 1993
Research Summary
My major research interests lie in the atomic resolution three-dimensional structure determination of single protein and multi-protein complexes important in human disease by X-ray crystallography. Currently my research focuses on the structural biology of the human HIV-1 accessory protein Nef in complex with cellular target proteins and small-molecule antagonists. I am working to determine the X-ray crystal structures of Nef in complexes with the Src-family kinases (Hck, Lyn and c-Src), Tec-family kinases (Itk and Bmx) and the PACS-2 trafficking protein. These protein interactions are essential for high-titer viral replication and immune evasion of HIV-infected cells. This structural biology effort has recently led to the structure determination of Nef in complex with the Hck SH3-SH2 regulatory domains, demonstrating how the Nef dimer is ordered for kinase activation and effector protein recruitment. In addition to these Nef:cellular target protein complexes, a structural biology effort to determine the crystal structures of Nef in complex with novel small molecule ligands recently discovered by our group is currently in progress. These studies will not only advance our knowledge of Nef function but are also essential to our longer-term goal to develop anti-retroviral compounds that target Nef.
Research Lab Affiliation
Publications
Alvarado J. J; Tarafdar S; Yeh J. I; and Smithgall, T.E. (2014) Interaction with the Src Homology (SH3-SH2) Region of the Src-family Kinase Hck Structures the HIV-1 Nef Dimer for Kinase Activation and Effector Recruitment. J Biol Chem. 289: 28539-28553. | View Abstract
Trible R. P; Narute P; Emert-Sedlak L. A; Alvarado J. J; Atkins K; Thomas L; Kodama T; Yanamala N; Korotchenko V; Day B. W; Thomas G; and Smithgall T. E. (2013) Discovery of a diaminoquinoxaline benzenesulfonamide antagonist of HIV-1 Nef function using a yeast-based phenotypic screen. Retrovirology. 10: 135. | View Abstract
Emert-Sedlak LA, Narute P, Shu ST, Poe JA, Shi H, Yanamala N, Alvarado JJ, Lazo JS, Yeh JI, Johnston PA and Smithgall TE. 2013. Effector kinase coupling enables high-throughput screens for direct HIV-1 Nef antagonists with antiretroviral activity. Chem Biol. 20: 82-91. | View Abstract
Pene-Dumitrescu T; Shu S. T; Wales T. E; Alvarado J. J; Shi H; Narute P; Moroco J. A; Yeh J. I; Engen J. R. and Smithgall, T. E. (2012) HIV-1 Nef interaction influences the ATP-binding site of the Src-family kinase, Hck. BMC Chem Biol. 12: 1. | View Abstract
Alvarado J. J; Betts L; Moroco J. A; Smithgall T. E; and Yeh, J. I. (2010) Crystal structure of the Src family kinase Hck SH3-SH2 linker regulatory region supports an SH3-dominant activation mechanism. J. Biol. Chem. 285: 35455-35461. | View Abstract
Alvarado J. J; Nemkal A; Sauder J. M; Russell M; Akiyoshi D. E; Shi W; Almo S. C; and Weiss L. M. (2009) Structure of a microsporidian methionine aminopeptidase type 2 complexed with fumagillin and TNP-470. Mol Biochem Parasitol. 168: 158-167. | View Abstract
Almo S. C; Bonanno J. B; Sauder J. M; Emtage S; Dilorenzo T. P; Malashkevich V; Wasserman S. R; Swaminathan S; Eswaramoorthy S; Agarwal R; Kumaran D; Madegowda M; Ragumani S; Patskovsky Y; Alvarado J; Ramagopal U. A; Faber-Barata J; Chance M. R; Sali A; Fiser A; Zhang Z. Y; Lawrence D. S; and Burley S. K. (2007) Structural genomics of protein phosphatases. J Struct Funct Genomics. 8: 121-140. | View Abstract