The mission of the Laboratory of Biomolecular Recognition is to explore at the molecular level the relationship between structure and function of proteins involved in HIV-1 infection, innate and adaptive immune responses, and tumorgenesis. To accomplish our goals we employ structural tools such as X-ray crystallography and bioinformatics in combination with protein engineering and functional analysis. Our current research is focused on three major themes:
Growing evidence points toward an important role of antibody-dependent cell mediated cytotoxicity (ADCC) in the anti-HIV-1 Env antibody response during infection. In collaboration with Laboratory of Humoral Immunity we elucidate the molecular basis for antigen recognition by non-neutralizing but potent ADCC-active mAbs isolated from HIV-1 infected individuals. Our work structurally dissects at the atomic level the functionally conserved surface of gp120 envelope glycoprotein that is involved in Fc-mediated effector function.
Defensins are a family of small, cationic and cysteine-rich antimicrobial peptides (AMPs) that act as innate effector molecules against the onslaught of microbial pathogens such as casual bacteria, fungi, enveloped and non-enveloped viruses, including HIV-1. The long-term objective of the defensin project is to apply X-ray crystallography, biochemical and biophysical techniques as well as biological activity assays to understand the functional role of defensin oligomerization and to determine the structural determinants of their interaction with viruses and bacteria.
Oncoproteins MDM2 (an E3 ubiquitin ligase) and its homolog MDMX (also known as MDM4) are key negative regulators of the p53 tumor suppressor. In many tumors, the presence of wild type p53 strongly correlates to amplification and/or over-expression of MDM2/MDMX, resulting directly in p53 suppression and malignant progression. MDM2 and MDMX bind with high affinity to the N-terminal transactivation domain of p53. Antagonizing MDM2 and/or MDMX to displace p53 from the inhibitory complex leads to p53 activation and kills tumor cells through cell cycle arrest, senescence or apoptosis. We are collaborating with Dr. Wuyuan Lu’s laboratory to design and structurally characterize various peptide antagonists of MDM2 and MDMX as p53 activators for potential anticancer therapy.
Liu M, Pazgier M, Li C, Yuan W, Li C, Lu W. (2010) A left-handed solution to peptide inhibition of the p53-MDM2 interaction., Angew Chem Int Ed Engl. 49(21):3649-52.
Liu M, Li C, Pazgier M, Li C, Mao Y, Lv Y, Gu B, Wei G, Yuan W, Zhan C, Lu WY, Lu W. (2010) D-peptide inhibitors of the p53-MDM2 interaction for targeted molecular therapy of malignant neoplasms., Proc Natl Acad Sci U S A, 107(32):14321-6.
Wei G, Pazgier M, de Leeuw E, Rajabi M, Li J, Zou G, Jung G, Yuan W, Lu WY, Lehrer RI, Lu W. (2010) Trp-26 imparts functional versatility to human alpha-defensin HNP1. J Biol Chem. 285(21):16275-85
Li C, Pazgier M, Li C, Yuan W, Liu M, Wei G, Lu WY, Lu W.(2010) Systematic mutational analysis of peptide inhibition of the p53-MDM2/MDMX interactions., J Mol Biol. 398(2):200-13.
Pazgier M, Liu M, Zou G, Yuan W, Li C, Li C, Li J, Monbo J, Zella D, Tarasov S. G, Lu W. (2009) Structural basis for high-affinity inhibition of p53 interactions with MDM2 and MDMX., Proc Natl Acad Sci U S A, 106(12):4665-70
Li C, Pazgier M, Liu M, Lu WY, Lu W. (2009) Apamin as a template for structure-based rational design of potent peptide activators of p53., Angew Chem Int Ed Engl. 48(46):8712-5
Wei G, de Leeuw E, Pazgier M, Yuan W, Zou G, Wang J, Ericksen B, Lu WY, Lehrer RI, Lu W. (2009) Through the looking glass, mechanistic insights from enantiomeric human defensins. J Biol Chem. 16;284(42):29180-92.