John J. Alvarado, PhD

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

Smithgall Lab