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Targeting protein–protein interactions by rational design: mimicry of protein surfaces

Steven Fletcher, +1 more
- 22 Apr 2006 - 
- Vol. 3, Iss: 7, pp 215-233
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TLDR
This review discusses this progress in the context of mimicry of protein surfaces: targeting protein–protein interactions by rational design in response to the large interfacial areas involved and the relatively flat and featureless topologies of these surfaces.
Abstract
Protein–protein interactions play key roles in a range of biological processes, and are therefore important targets for the design of novel therapeutics. Unlike in the design of enzyme active site inhibitors, the disruption of protein–protein interactions is far more challenging, due to such factors as the large interfacial areas involved and the relatively flat and featureless topologies of these surfaces. Nevertheless, in spite of such challenges, there has been considerable progress in recent years. In this review, we discuss this progress in the context of mimicry of protein surfaces: targeting protein–protein interactions by rational design.

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Safety and antiretroviral activity of chronic subcutaneous administration of t-20 in human immunodeficiency virus 1-infected children

Joseph A. Church
- 01 Aug 2003 - 
TL;DR: The use of combination antiretroviral therapy has been associated with a substantial decline in morbidity and mortality in human immunodeficiency virus (HIV)-infected individuals and pharmacologic agents effective at alternative stages in the replication cycle of the virus are identified.
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Metal-directed protein self-assembly.

TL;DR: This approach, of metal templating followed by the redesign of protein interfaces (metal-templated interface redesign, MeTIR), not only provides a route to engineer de novo PPIs and novel metal coordination environments but also suggests possible parallels with the evolution of metalloproteins.
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Can Self-Inhibitory Peptides be Derived from the Interfaces of Globular Protein-Protein Interactions?

TL;DR: This study assesses on a large scale the possibility of deriving self‐inhibitory peptides from protein domains with globular architectures and provides an elaborate framework for the in silico selection of candidate inhibitory molecules for protein–protein interactions.
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Inhibition of Mcl-1 through covalent modification of a noncatalytic lysine side chain

TL;DR: The first reversible covalent inhibitors for Mcl-1, a protein-protein interaction (PPI) target that has proven difficult to inhibit via traditional medicinal chemistry strategies, are generated using aryl boronic acid carbonyl warheads to covalently target a noncatalytic lysine side chain.
References
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p53, guardian of the genome

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The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus

TL;DR: It is concluded that the CD4 antigen is an essential and specific component of the receptor for the causative agent of AIDS.
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Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody

TL;DR: The structure reveals a cavity-laden CD4–gp120 interface, a conserved binding site for the chemokine receptor, evidence for a conformational change upon CD4 binding, the nature of a CD4-induced antibody epitope, and specific mechanisms for immune evasion.
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Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain.

TL;DR: The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to a 15-Residue transactivation domain peptide of p53 revealed that MDM 2 has a deep hydrophobic cleft on which the p53 peptide binds as an amphipathic α helix, supporting the hypothesis thatMDM2 inactivates p53 by concealing its transactivationdomain.
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Amplification of a gene encoding a p53-associated protein in human sarcomas

TL;DR: Results are consistent with the hypothesis thatMDM2 binds to p53, and that amplification of MDM2 in sarcomas leads to escape from p53-regulated growth control, and this mechanism of tumorigenesis parallels that for virally-induced tumours.
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