Front Cover

Protein-Protein Interactions in Human Disease, Part B

Copyright

Contents

Contributors

Preface

Chapter One: Homo- and Heterodimerization of Proteins in Cell Signaling: Inhibition and Drug Design

1. Introduction

2. Methods to Study PPIs and Their Inhibition

2.1. Coimmunoprecipitation

2.2. Pull-Down Assay

2.3. Proximity Ligation Assay

2.4. Enzyme Fragment Complementation Assay (PathHunter Assay)

2.5. Surface Plasmon Resonance

2.6. Mutational Studies to Identify Hot Spots in PPI

3. Inhibition of Dimerization of Protein and PPI

4. Design of Compounds Based on Protein Interface

4.1. Structure-Based Drug Design

4.2. Fragment-Based Discovery in PPI Inhibition

4.3. High-Throughput Screening

5. Homodimers

5.1. G-Protein-Coupled Receptors

5.2. Receptor Tyrosine Kinase-Like Orphan Receptor 2

5.3. Glucocorticoid Receptor

5.4. Amyloid Precursor Protein Dimers

5.5. EGFR Homodimers

6. Heterodimerization of Proteins and Inhibition

6.1. p45-p75 Heterodimers

6.2. IL-6-IL-6Rα

6.3. Epidermal Growth Factor Receptors

6.3.1. Structure of ECDs of Proteins

6.3.2. Design Concept

6.4. PD-1-PD-L1 Pathway

6.5. CD-28/CD-80

6.6. CD2-CD58 Interactions and the Design of Multicyclic Peptides

6.6.1. Multicyclic Peptide Approach

References

Chapter Two: Targeting Intramembrane Protein-Protein Interactions: Novel Therapeutic Strategy of Millions Years Old

1. Introduction

2. PPIs in Transmembrane Signaling

2.1. Intramembrane and Cytoplasmic Interactions

2.1.1. Single-Chain Receptors

2.1.2. Multichain Receptors

2.2. Transmembrane Signaling and Viral Evasion Strategies: Evolutionary and Molecular Aspects

3. Intramembrane PPIs as a Therapeutic Target

3.1. Cancer

3.1.1. Nonsmall Cell Lung Cancer

3.1.2. Pancreatic Cancer

3.2. Autoimmune Diseases

3.2.1. Targeting T Cell Receptor

3.2.2. Targeting TREM-1

3.3. Sepsis

3.4. Thrombosis

3.5. Retinopathy

4. Conclusions

Acknowledgments

References

Further Reading

Chapter Three: Targeting the Architecture of Deregulated Protein Complexes in Cancer

1. Introduction

2. RAS:RAF Signalosome and Network

2.1. Background

2.2. Small G Proteins of the RAS Family and RAF Family Serine-Threonine Kinases

2.3. Physiological and Pathophysiological Functions

2.4. Pharmacological Targeting of RAS:RAF Complexes

3. PKA Signalosome and Network

3.1. Background

3.2. Macromolecular PKA Complexes

3.3. Pathological PKA Functions

3.4. Pharmacological Targeting of PKA Emanating PPIs

4. MYC:MAX Signalosome and Network

4.1. The MYC:MAX Network

4.2. Physiological and Oncogenic Functions

4.3. Pharmacological Interference

5. Conclusions

Acknowledgments

References

Chapter Four: Multifaceted Nucleolin Protein and Its Molecular Partners in Oncogenesis

1. Introduction

2. Structure of Nucleolin

3. Role of Nucleolin in Ribosome Biogenesis and Gene Expression in Cancer Cells

4. Functions of Nucleolin in DNA Repair and Genome Stability

5. Functions of Nucleolin in Cell Division

6. Functions of Nucleolin in Cell Survival

7. Nucleolin Function in Chemokine Receptor Signaling

8. Function of Nucleolin in EGF-TGF-β Signaling Pathways

9. Nucleolin on Angiogenesis and Lymphangiogenesis

10. Nucleolin Function in Epithelial-Mesenchymal Transition

11. Nucleolin Functions in Stemness

12. Concluding Remarks

Acknowledgments

References

Chapter Five: Subcellular Targeting of Nitric Oxide Synthases Mediated by Their N-Terminal Motifs

1. Nitric Oxide and Nitric Oxide Synthases

2. Subcellular Targeting of iNOS Mediated by N-Terminal Palmitoylation

3. N-Terminal eNOS Myristoylation and Palmitoylation Mediate Its Subcellular Localization

4. nNOS and Its Multiple N-Terminal Localization Signals

5. The PDZ Domain of nNOS and Its Interacting Proteins

6. Understanding the Promiscuity of Binding Shown by the PDZ Domain of nNOS

7. nNOS as a Target in Excitotoxicity

8. nNOS as a Target in Duchenne Muscular Dystrophy

9. Final Remarks

References

Chapter Six: Development of Protein-Protein Interaction Inhibitors for the Treatment of Infectious Diseases

1. Antibacterial Agents

1.1. ZipA-FtsZ

1.2. Pilicides

1.3. DnaN-DnaE1

2. Antiviral PPI Inhibitors

2.1. Human Papillomavirus Ori-E1-E2 Interaction

2.2. Human Immunodeficiency Virus

2.3. HIV Entry Inhibitors

2.4. HIV Integrase Inhibitors

3. Targeting Host-Host PPIs to Improve Infection Survival

3.1. Neutrophil Exocytosis Inhibitors (Nexinhibs)

4. Considerations for Targeting PPIs

References

Chapter Seven: Defining Pharmacological Targets by Analysis of Virus-Host Protein Interactions

1. Cellular Proteins Exist in Complexes

2. Discovering Virus-Host Protein Complexes

3. Different Pathogens Exploit Similar Cellular Processes

4. Viral Proteins Interact With Host Proteins in Complexes

5. Development of Small Molecules Disrupting PPIs

6. Targeting Virus-Host PPIs With Small Molecules

7. Small Molecules Disrupting Host Complexes Implicated in Viral Replication

8. Concluding Remarks

Acknowledgments

References

Chapter Eight: Investigating the Influence of Hotspot Mutations in Protein-Protein Interaction of IDH1 Homodimer Protein: ...

1. Introduction

2. Materials and Methods

2.1. Dataset and Protein Modeling

2.2. Conservation and Pathogenicity Analysis

2.3. Stability Analysis

2.4. Molecular Docking and Molecular Dynamics Simulations

3. Results

3.1. Protein-Protein Interaction

3.2. Conservation and Pathogenicity Analysis

3.3. Stability Analysis

3.4. Molecular Docking Analysis

3.5. Molecular Dynamics Simulations (MDS)

4. Discussion

5. Conclusion

Acknowledgments

References

Chapter Nine: Human Interactomics: Comparative Analysis of Different Protein Interaction Resources and Construction of a ...

1. Introduction

2. Primary Databases of PPIs

3. Meta-databases Integrating and Unifying Multiple PPI Resources

4. Human Interactome: Proteome-Wide Human PPI Compendiums

5. Human Drug-Target Interaction Resources

6. Cancer Genes/Proteins Compendium

7. Construction of a PPI Network With Cancer Genes

8. Cancer Protein-Drug Bipartite Network Reveals Druggable Modules

References

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