Allosteric modulation of kinases and GPCRs: design principles and structural diversity.

Abstract:

:Allosteric binding sites, as opposed to traditional orthosteric binding sites, offer unparalleled opportunities for drug discovery by providing high levels of selectivity, mimicking physiological conditions, affording fewer side effects because of desensitization/downregulation, and engendering ligands with chemotypes divergent from orthosteric ligands. For kinases, allosteric mechanisms described to date include alteration of protein kinase conformation blocking productive ATP binding which appear 'ATP competitive' or blocking kinase activation by conformational changes that are 'ATP non-competitive'. For GPCRs, allosteric mechanisms impart multiple modes of target modulation (positive allosteric modulation (PAM), negative allosteric modulation (NAM), neutral cooperativity, partial antagonism (PA), allosteric agonism and allosteric antagonism). Here, we review recent developments in the design principles and structural diversity of allosteric ligands for kinases and GPCRs.

journal_name

Curr Opin Chem Biol

authors

Lewis JA,Lebois EP,Lindsley CW

doi

10.1016/j.cbpa.2008.02.014

subject

Has Abstract

pub_date

2008-06-01 00:00:00

pages

269-80

issue

3

eissn

1367-5931

issn

1879-0402

pii

S1367-5931(08)00035-5

journal_volume

12

pub_type

杂志文章,评审
  • Photorespiration and the potential to improve photosynthesis.

    abstract::The photorespiratory pathway, in short photorespiration, is an essential metabolite repair pathway that allows the photosynthetic CO2 fixation of plants to occur in the presence of oxygen. It is necessary because oxygen is a competing substrate of the CO2-fixing enzyme ribulose 1,5-bisphosphate carboxylase, forming 2-...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2016.09.014

    authors: Hagemann M,Bauwe H

    更新日期:2016-12-01 00:00:00

  • Steroid 5alpha-reductase inhibitors in androgen-dependent disorders.

    abstract::Inhibition of the steroid 5alpha-reductases shows promise in the treatment of a number of androgen-dependent disorders, such as benign prostatic hyperplasia, male pattern baldness, and acne. The design of potent and isozyme-selective inhibitors has provided biologists and clinicians with important tools for elucidatin...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/s1367-5931(97)80017-8

    authors: Harris GS,Kozarich JW

    更新日期:1997-08-01 00:00:00

  • Following the Ca²⁺ roadmap to photocaged complexes for Zn²⁺ and beyond.

    abstract::The first photocaged complexes appeared in the mid-1980s specifically to complement the ongoing work studying intracellular Ca(2+) signaling with fluorescent probes. Recently, the field of biological inorganic chemistry has focused increasingly on the homeostasis mechanisms and possible signaling functions of transiti...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2012.11.015

    authors: Gwizdala C,Burdette SC

    更新日期:2013-04-01 00:00:00

  • Making drugs on proteins: site-directed ligand discovery for fragment-based lead assembly.

    abstract::Rapid progress in genomics and proteomics has provided a wealth of new targets for the pharmaceutical industry, even as many older targets still remain challenging for small-molecule drug discovery. Fragment-based lead discovery, in which leads are built progressively by expanding or combining small fragments, is a ra...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2004.06.010

    authors: Erlanson DA,Hansen SK

    更新日期:2004-08-01 00:00:00

  • Chemotherapeutic potential of phosphodiesterase inhibitors.

    abstract::The application of molecular cloning has revealed the phenomenal diversity and complexity of the phosphodiesterase isoenzyme family. Thus, more than 30 human phosphodiesterases are now known; all are apparently necessary for the seemingly simple task of hydrolysing the 3'-ester bond of either cyclic adenosine monophos...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/s1367-5931(98)80123-3

    authors: Perry MJ,Higgs GA

    更新日期:1998-08-01 00:00:00

  • Fresh insight to functioning of selected enzymes of the nitrogen cycle.

    abstract::The global nitrogen cycle is the process in which different forms of environmental N are interconverted by microorganisms either for assimilation into biomass or in respiratory energy-generating pathways. This short review highlights developments over the last 5 years in our understanding of functionality of nitrogena...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2016.02.009

    authors: Eady RR,Antonyuk SV,Hasnain SS

    更新日期:2016-04-01 00:00:00

  • Modern methods to produce natural-product libraries.

    abstract::Natural sources offer a wealth of chemically diverse compounds that have been evolutionary preselected to modulate biochemical pathways. Several industrial and academic groups are accessing this source using advanced technology platforms. Methods have been reported to generate large and diverse natural-product librari...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/s1367-5931(02)00338-1

    authors: Abel U,Koch C,Speitling M,Hansske FG

    更新日期:2002-08-01 00:00:00

  • PNA-encoded chemical libraries.

    abstract::Peptide nucleic acid (PNA)-encoded chemical libraries along with DNA-encoded libraries have provided a powerful new paradigm for library synthesis and ligand discovery. PNA-encoding stands out for its compatibility with standard solid phase synthesis and the technology has been used to prepare libraries of peptides, h...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2015.01.005

    authors: Zambaldo C,Barluenga S,Winssinger N

    更新日期:2015-06-01 00:00:00

  • Synthetic developmental biology: build and control multicellular systems.

    abstract::Synthetic biology offers a bottom-up engineering approach that intends to understand complex systems via design-build-test cycles. Embryonic development comprises complex processes that originate at the level of gene regulatory networks in a cell and emerge into collective cellular behaviors with multicellular forms a...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2019.04.006

    authors: Ebrahimkhani MR,Ebisuya M

    更新日期:2019-10-01 00:00:00

  • Functional protein microarrays: ripe for discovery.

    abstract::The manufacture and use of protein microarrays with correctly folded and functional content presents significant challenges. Despite this, the feasibility and utility of such undertakings are now clear, and exciting progress has recently been demonstrated in the areas of content generation, printing strategies and pro...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2003.12.005

    authors: Predki PF

    更新日期:2004-02-01 00:00:00

  • New approaches for cell-specific targeting: identification of cell-selective peptides from combinatorial libraries.

    abstract::Peptides that recognize specific cell types promise to be valuable tools both in research and clinical applications. Cell-specific peptides can be useful as drug delivery vehicles, diagnostic agents, affinity reagents for cell purification, gene therapy delivery agents, and research tools to probe the nature of a cell...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/s1367-5931(99)00045-9

    authors: Brown KC

    更新日期:2000-02-01 00:00:00

  • Proteomic approaches to the characterization of protein thiol modification.

    abstract::Protein cysteine residues are central to redox signaling and to protection against oxidative damage through their interactions with reactive oxygen and nitrogen species, and electrophiles. Although there is considerable evidence for a functional role for cysteine modifications, the identity and physiological significa...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2010.11.003

    authors: Chouchani ET,James AM,Fearnley IM,Lilley KS,Murphy MP

    更新日期:2011-02-01 00:00:00

  • Protein epitope mimetics as anti-infectives.

    abstract::There is growing interest in the design of synthetic molecules that mimic the structures and functions of epitopes found on the surface of peptides and proteins. Epitope mimetics can provide valuable tools to probe complex biological processes, as well as interesting leads for drug and vaccine discovery. One applicati...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2011.02.015

    authors: Robinson JA

    更新日期:2011-06-01 00:00:00

  • Anti-integrin as novel drug-discovery targets: potential therapeutic and diagnostic implications.

    abstract::The role of integrin and extracellular matrix proteins in various pathological processes (including angiogenesis, thrombosis, apoptosis and cell migration and proliferation), leading to both acute and chronic disease states (e.g. ocular diseases, metastasis, unstable angina, myocardial infarction, stroke, osteoporosis...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/s1367-5931(02)00350-2

    authors: Mousa SA

    更新日期:2002-08-01 00:00:00

  • Peptide mediated formation of noble metal nanoparticles-controlling size and spatial arrangement.

    abstract::Over the past two decades, peptides have expanded the toolbox of additives for the preparation of noble metal nanoparticles. Their functional and structural modularity and accompanying molecular recognition and self-assembly properties offer unique opportunities for the controlled formation of NPs. Within this review,...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2017.09.005

    authors: Corra S,Shoshan MS,Wennemers H

    更新日期:2017-10-01 00:00:00

  • The joys of in vitro selection: chemically dressing oligonucleotides to satiate protein targets.

    abstract::Oligonucleotide in vitro selection provides surprisingly specific aptamers to protein targets. Synthetic chemistries for modifying nucleotides have been developed to enhance aptamer binding affinity. The diversity of nucleosides amenable to either triphosphate synthesis or phosphoramidite activation is now sufficientl...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/s1367-5931(97)80103-2

    authors: Eaton BE

    更新日期:1997-06-01 00:00:00

  • Phosphorescence bioimaging using cyclometalated Ir(III) complexes.

    abstract::Recent advances in the development of the phosphorescent Ir(III) complexes have made it possible to implement the phosphorescence modality in bioimaging applications. A variety of phosphorescent Ir(III) complexes have been synthesized and assessed in the context of in vitro and in vivo imaging, especially in subcellul...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2013.05.023

    authors: You Y

    更新日期:2013-08-01 00:00:00

  • Covalent protein modification: the current landscape of residue-specific electrophiles.

    abstract::Functional amino acids that play critical roles in catalysis and regulation are known to display elevated nucleophilicity and can be selectively targeted for covalent modification by reactive electrophiles. Chemical-proteomic platforms, such as activity-based protein profiling (ABPP), exploit this reactivity by utiliz...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2014.10.021

    authors: Shannon DA,Weerapana E

    更新日期:2015-02-01 00:00:00

  • Optical spectroscopy for detection of neoplasia.

    abstract::Fluorescence and reflectance spectroscopy provide the ability to assess tissue structure and metabolism in vivo in real time, providing improved diagnosis of pre-cancerous lesions. Reflectance spectroscopy can probe changes in epithelial nuclei that are important in pre-cancer detection, such as mean nuclear diameter,...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/s1367-5931(02)00381-2

    authors: Sokolov K,Follen M,Richards-Kortum R

    更新日期:2002-10-01 00:00:00

  • Protein tyrosine phosphatases: mechanisms of catalysis and regulation.

    abstract::Recent structural information suggests that the HC(X)5R active-site motif defines three distinct evolutionary families of phosphatases that employ a common catalytic mechanism. In two instances, regulation of phosphatase activity employs autoinhibitory mechanisms involving either intermolecular or intramolecular inter...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/s1367-5931(98)80095-1

    authors: Denu JM,Dixon JE

    更新日期:1998-10-01 00:00:00

  • Advances in design of protein folds and assemblies.

    abstract::Conceptual and computational advances triggered an explosion of designed protein structures in the recent years. Various protein fold geometries have been robustly designed with atomic accuracy, including protein folds unseen in nature. The same principles and tools have been extended to design multi-chain assemblies....

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2017.06.020

    authors: Ljubetič A,Gradišar H,Jerala R

    更新日期:2017-10-01 00:00:00

  • Unlocked potential of dynamic elements in protein structures: channels and loops.

    abstract::Enzymes are nature's powerful catalytic proteins to perform reactions with often outstanding activity, selectivity and specificity. Moreover, the access to non-natural functions of biocatalysts can be facilitated by enzyme engineering. While rational approaches are often focused on an enzyme's active site, from random...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2018.09.010

    authors: Kreß N,Halder JM,Rapp LR,Hauer B

    更新日期:2018-12-01 00:00:00

  • Recent advances in heme-protein sensors.

    abstract::In recent years, an increasing number of proteins have been discovered which utilize heme cofactors to sense oxygen, carbon monoxide and nitric oxide. The identification and characterization of these proteins are revising our understanding of heme-mediated allostery first established in the early 1960s. Biochemical an...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/s1367-5931(00)00193-9

    authors: Chan MK

    更新日期:2001-04-01 00:00:00

  • Function of genetically encoded pyrrolysine in corrinoid-dependent methylamine methyltransferases.

    abstract::Methanogenesis from trimethylamine, dimethylamine or monomethylamine is initiated by a series of corrinoid-dependent methyltransferases. The non-homologous genes encoding the full-length methyltransferases each possess an in-frame UAG (amber) codon that does not terminate translation. The amber codon is decoded by a d...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2004.08.012

    authors: Krzycki JA

    更新日期:2004-10-01 00:00:00

  • Activity-based sensing fluorescent probes for iron in biological systems.

    abstract::Iron is an essential nutrient for life, and its capacity to cycle between different oxidation states is required for processes spanning oxygen transport and respiration to nucleotide synthesis and epigenetic regulation. However, this same redox ability also makes iron, if not regulated properly, a potentially dangerou...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2017.12.010

    authors: Aron AT,Reeves AG,Chang CJ

    更新日期:2018-04-01 00:00:00

  • Oligosaccharyl transferase: gatekeeper to the secretory pathway.

    abstract::Oligosaccharyl transferase is part of the macromolecular machinery that processes nascent proteins in the endoplasmic reticulum. The enzyme is highly conserved, catalyzes the initial step in the biosynthesis of N-linked glycoproteins and acts as a 'gatekeeper' for the secretory pathway. As more proteins associated wit...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/s1367-5931(02)00390-3

    authors: Dempski RE Jr,Imperiali B

    更新日期:2002-12-01 00:00:00

  • The chemokine/chemokine-receptor family: potential and progress for therapeutic intervention.

    abstract::The chemokines are a large superfamily of chemotactic cytokines that are utilized to direct the trafficking and migration of leukocytes within the immune system. The chemokines mediate their activity through a large family of G-protein-coupled receptors, and thus are highly tractable as therapeutic targets. Exciting a...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/s1367-5931(00)00113-7

    authors: Cascieri MA,Springer MS

    更新日期:2000-08-01 00:00:00

  • Target deconvolution techniques in modern phenotypic profiling.

    abstract::The past decade has seen rapid growth in the use of diverse compound libraries in classical phenotypic screens to identify modulators of a given process. The subsequent process of identifying the molecular targets of active hits, also called 'target deconvolution', is an essential step for understanding compound mecha...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2012.12.022

    authors: Lee J,Bogyo M

    更新日期:2013-02-01 00:00:00

  • Synthetic biology for natural product drug production and engineering.

    abstract::Natural products continue to provide privileged scaffolds for drug discovery. However, challenges in supply and structure diversification can limit development. Here, we discuss recent (2017-2020) examples of synthetic biology approaches used to address challenges in supply and contribute to structure diversification ...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2020.09.006

    authors: Romanowski S,Eustáquio AS

    更新日期:2020-10-01 00:00:00

  • Coupled motions in enzyme catalysis.

    abstract::Recently, the hypothesis that protein motions are involved in enzymatic turnover has gained significant attention. We review cases where there is evidence that protein motions are rate-limiting in the overall catalytic cycle and examine experimental and theoretical evidence for how such motions enhance the probability...

    journal_title:Current opinion in chemical biology

    pub_type: 杂志文章,评审

    doi:10.1016/j.cbpa.2010.07.020

    authors: Nashine VC,Hammes-Schiffer S,Benkovic SJ

    更新日期:2010-10-01 00:00:00