Structural Biology and Drug Discovery

Scapin, Giovanna

doi:10.2174/138161206777585201

Cited by 111 publications

(53 citation statements)

References 86 publications

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“…Structural bioinformatics which integrates structural biology and bioinformatics is revolutionizing the process of drug discovery. [44][45][46] Now, fewer steps are needed to find new drugs: characterization of a protein target, modeling the protein using sequence homology, optimization of the protein structure, and finally docking of small ligands into the active site. Incorporating these features of structural bioinformatics into drug discovery, in silico approaches for identifying potential drug candidates can be virtually screened at a high speed.…”

Section: Discussionmentioning

confidence: 99%

Targeting Therapy for Breast Carcinoma by ATP Synthase Inhibitor Aurovertin B

et al. 2008

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Targeting of tumor tissues is one of the most powerful approaches to accelerate the efficiency of anticancer treatments. The investigation of effective targets, including proteins specifically and abundantly expressed in abnormal regions, has been one of the most important research topics in cancer therapy. In this study, we performed a proteomic analysis on human breast carcinoma tissues to investigate the tumor-specific protein expression in breast carcinoma. Our study showed that ATP synthase was up-regulated in tumor tissues and was present on the plasma membrane of breast cancer cells. Furthermore, we treated the breast cancer cells with ATP synthase inhibitors and examined the inhibitory efficiency. Aurovertin B, an ATP synthase inhibitor, has strong inhibition on the proliferation of several breast cancer cell lines, but little influence on the normal cell line MCF-10A. Aurovertin B inhibits proliferation of breast cancer cells by inducing apoptosis and arresting cell cycle at the G0/G1 phase. This study showed aurovertin B can be used as an antitumorigenic agent and may be exploited in cancer chemotherapy.

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Section: Discussionmentioning

confidence: 99%

Targeting Therapy for Breast Carcinoma by ATP Synthase Inhibitor Aurovertin B

et al. 2008

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“…Investigation of the functional roles of specific proprotein-protease interactions may reveal strategies to disrupt such interactions, thereby resulting in selective inhibition of proneuropeptide or prohormone processing. Furthermore, the combination of protein structural studies by crystallography (102,103), CD (104,105), H-D exchange (hydrogen-deuterium exchange) (106,107), and related approaches for defining protein structures will be fruitful for understanding structural features of how proneuropeptide interact with processing proteases for production of active neuropeptides.…”

Section: Structural Biology Of Proteases and Proneuropeptides (Prohormentioning

confidence: 99%

Proteases for Processing Proneuropeptides into Peptide Neurotransmitters and Hormones

Hook

Funkelstein

et al. 2008

Annu. Rev. Pharmacol. Toxicol.

221

304

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Summary Points List:1. Proteases are essential for proteolytic processing of proneuropeptide precursors into active peptide neurotransmitters and hormones.2. Secretory vesicles represent the primary subcellular site of neuropeptide biosynthesis, which are produced, stored, and secreted to mediate cell-cell communication. 3.Protease pathways for proneuropeptide processing have been elucidated consisting of (a) the newly identified cysteine protease cathepsin L with aminopeptidase B in secretory vesicles, and (b) the well-established, proprotein convertase family that include the neuroendocrine-specific prohormone convertases 1 and 2 (PC1/3 and PC2) with carboxypeptidase E. 4.Protease gene knockout experiments have validated the roles of PC1/3, PC2, as well as cathepsin L for the production of neuropeptides in nervous and endocrine tissues. 5.Endogenous regulators consisting of inhibitors and activators participate in the in vivo control of processing enzyme functions.6. Structural biology of protease and proneuropeptides will be important to understand interacting mechanisms for proneuropeptide processing. 7.Neuropeptidomics has recently been applied to investigations of neuropeptide systems for their primary sequence and structural identification, as well as quantitation by LC-MS/MS tandem mass spectrometry. 8.Proteomic studies have revealed functional protein families that participate in secretory vesicle functions for the production, storage, and secretion of neuropeptides.9. Pharmacological evaluation of unique specificities among neuropeptide processing systems will be valuable for design of future strategies to develop selective small molecule modulators of processing enzymes for therapeutic applications in health and disease.Future Issues: Areas of Neuropeptide Research for Exploration. 1.How are cathepsin L and prohormone convertase protease pathways coordinately regulated? 2.What is the proteolytic basis for tissue-specific processing of proneuropeptides, such as that for POMC?3. Selective and potent inhibitors of protease components for processing prohormones should be developed to facilitate basic and pharmacological research. 4.What are the structural features of prohormone and protease interactions for functional processing? Peptide neurotransmitters and peptide hormones, collectively known as neuropeptides, are required for cell-cell communication in neurotransmission and for regulation of endocrine functions. Neuropeptides are synthesized from protein precursors (termed proneuropeptides or prohormones) that require proteolytic processing primarily within secretory vesicles that store and secrete the mature neuropeptides to control target cellular and organ systems. This review describes interdisciplinary strategies that have elucidated two primary protease pathways for prohormone processing consisting of the cysteine protease pathway mediated by secretory vesicle cathepsin L and the well-known subtilisin-like proprotein convertase pathway that together support neuropeptide biosynthesis. Importantly...

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“…Structure based drug design is a valid approach towards the identification of small molecule inhibitors of protein-protein interactions [24]. The identification of drugable protein-protein interactions represents an important avenue in the drug discovery paradigm, as the number of protein targets that can be directly modulated by small molecule compounds or antibodies is rapidly declining [25].…”

Section: Introductionmentioning

confidence: 99%

Remedial strategies in structural proteomics: Expression, purification, and crystallization of the Vav1/Rac1 complex

Brooun

Foster

Chrencik

et al. 2007

Protein Expression and Purification

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The signal transduction pathway involving the Vav1 guanine nucleotide exchange factor (GEF) and the Rac1 GTPase plays several key roles in the immune response mediated by the T cell receptor. Vav1 is also a unique member of the GEF family in that it contains a cysteine-rich domain (CRD) that is critical for Rac1 binding and maximal guanine nucleotide exchange activity, and thus may provide a unique protein-protein interface compared to other GEF/GTPase pairs. Here we have applied a number of remedial structural proteomics strategies, such as construct and expression optimization, surface mutagenesis, limited proteolysis, and protein formulation to successfully express, purify, and crystallize the Vav1-DH-PH-CRD/Rac1 complex in an active conformation. We have also systematically characterized various Vav1 domains in a GEF assay, and Rac1 in vitro binding experiments. In the context of Vav1-DH-PH-CRD, the zinc finger motif of the CRD is required for the expression of stable Vav1, as well as for activity in both a GEF assay and in vitro formation of a Vav1/Rac1 complex suitable for biophysical and structural characterization. Our data also indicate that the isolated CRD maintains a low level of specific binding to Rac1, appears to be folded based on 1D-NMR analysis and coordinates two zinc ions based on ICP-MS analysis. The protein reagents generated here are essential tools for the determination of a three dimensional Vav1/ Rac1 complex crystal structure and possibly for the identification of inhibitors of the Vav1/Rac1 protein-protein interaction with potential to inhibit lymphocyte activation.

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Structural Biology and Drug Discovery

Cited by 111 publications

References 86 publications

Targeting Therapy for Breast Carcinoma by ATP Synthase Inhibitor Aurovertin B

Targeting Therapy for Breast Carcinoma by ATP Synthase Inhibitor Aurovertin B

Proteases for Processing Proneuropeptides into Peptide Neurotransmitters and Hormones

Remedial strategies in structural proteomics: Expression, purification, and crystallization of the Vav1/Rac1 complex

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