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Protein & Cell ; (12): 866-877, 2016.
Article in English | WPRIM | ID: wpr-757362


Antibody-based PD-1/PD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre-existing T-cell function to modulate antitumor immunity. In this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-1/PD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.

Antibodies, Monoclonal , Allergy and Immunology , Therapeutic Uses , Antibodies, Monoclonal, Humanized , Allergy and Immunology , Therapeutic Uses , B7-H1 Antigen , Allergy and Immunology , Humans , Neoplasms , Drug Therapy , Allergy and Immunology , Pathology , Programmed Cell Death 1 Receptor , Allergy and Immunology , Signal Transduction , Allergy and Immunology , T-Lymphocytes , Allergy and Immunology
Protein & Cell ; (12): 250-258, 2011.
Article in English | WPRIM | ID: wpr-757102


NDM-1 (New Delhi metallo-beta-lactamase) gene encodes a metallo-beta-lactamase (MBL) with high carbapenemase activity, which makes the host bacterial strain easily dispatch the last-resort antibiotics known as carbapenems and cause global concern. Here we present the bioinformatics data showing an unexpected similarity between NDM-1 and beta-lactamase II from Erythrobacter litoralis, a marine microbial isolate. We have further expressed these two mature proteins in E. coli cells, both of which present as a monomer with a molecular mass of 25 kDa. Antimicrobial susceptibility assay reveals that they share similar substrate specificities and are sensitive to aztreonam and tigecycline. The conformational change accompanied with the zinc binding visualized by nuclear magnetic resonance, Zn(2+)-bound NDM-1, adopts at least some stable tertiary structure in contrast to the metal-free protein. Our work implies a close evolutionary relationship between antibiotic resistance genes in environmental reservoir and in the clinic, challenging the antimicrobial resistance monitoring.

Amino Acid Sequence , Anti-Bacterial Agents , Pharmacology , Aztreonam , Pharmacology , Cephalosporinase , Chemistry , Genetics , Metabolism , Computational Biology , Methods , Drug Resistance, Bacterial , Genetics , Enzyme Stability , Evolution, Molecular , Minocycline , Pharmacology , Molecular Sequence Data , Phylogeny , Protein Structure, Tertiary , Sequence Homology, Nucleic Acid , Sphingomonadaceae , Genetics , Tigecycline , Zinc , Pharmacology , beta-Lactamases , Chemistry , Genetics , Metabolism