Small molecule inhibition of a Group II chaperonin: Pinpointing a loop region within the equatorial domain as necessary for protein refolding

Bergeron, Lisa M.; Shis, David L.; Gomez, Lizabeth; Clark, Douglas S.

doi:10.1016/j.abb.2008.10.016

Cited by 6 publications

(4 citation statements)

References 39 publications

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“…Epolactaene [191] inhibits GroEL through electrophilic reaction with Cys442, β-lactams are proposed to interact with a loop in the N-terminal region based upon docking simulations [192], and the sesquiterpene natural product suvanine [193] acts as a non-ATP-competitive chaperonin inhibitor, but its mechanism of action has not been fully characterized. The low availability of small-molecules that target areas outside of the chaperonin ATPase site, such as the protein-folding chamber, makes pursuit of such pharmacological modulators attractive because of the conceptually unique mechanism of action.…”

Section: Hsp60/chaperoninsmentioning

confidence: 99%

The Chemical Biology of Molecular Chaperones—Implications for Modulation of Proteostasis

Brandvold

Morimoto

2015

Journal of Molecular Biology

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Protein homeostasis (proteostasis) is inextricably tied to cellular health and organismal lifespan. Aging, exposure to physiological and environmental stress, and expression of mutant and metastable proteins can cause an imbalance in the protein folding landscape, resulting in the formation of non-native protein aggregates that challenge the capacity of the proteostasis network (PN), increasing the risk for diseases associated with misfolding, aggregation and aberrant regulation of cell stress responses. Molecular chaperones have central roles in each of the arms of the PN (protein synthesis, folding, disaggregation, and degradation), leading to the proposal that modulation of chaperone function could have therapeutic benefits for the large and growing family of diseases of protein conformation including neurodegeneration, metabolic diseases, and cancer. In this review, we will discuss the current strategies used to tune the PN through targeting molecular chaperones and assess the potential of the chemical biology of proteostasis.

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Section: Hsp60/chaperoninsmentioning

confidence: 99%

The Chemical Biology of Molecular Chaperones—Implications for Modulation of Proteostasis

Brandvold

Morimoto

2015

Journal of Molecular Biology

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“…Fluorescent DNA [92] Fluorescence anisotropy for binding of 6-aminopenicillanic acid to a chaperonin domain Fluorescein-coupled 6-amino-penicillanic acid [20] and deacylation of such mutant OXA-1 and OXA-10 β-lactamases, respectively. Extending this type of measurement to another class of β-lactam, June et al [22] used a fluorescein derivative of meropenem, a carbapenem, to perform fluorescence-based kinetic measurements of acylation of soluble constructs of PBP3 and β-lactam sensor protein BlaR1.…”

Section: Fluorescent Substance Referencesmentioning

confidence: 99%

“…Bergeron et al [20] used the increase in the fluorescence anisotropy of a fluorescein derivative of 6-aminopenicillanic acid (6-APA) to measure the affinity of this compound for a chaperonin protein of Methanocaldococcus jannaschii and localize its binding site. 6-APA is an inhibitor of the protein refolding activity of the chaperonin.…”

Section: Fluorescent Substance Referencesmentioning

confidence: 99%

Investigation ofβ-lactam antibacterial drugs,β-lactamases, and penicillin-binding proteins with fluorescence polarization and anisotropy: a review

Shapiro

2016

Methods Appl. Fluoresc.

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This review covers the uses of fluorescence polarization and anisotropy for the investigation of bacterial penicillin binding proteins (PBPs), which are the targets of β-lactam antibacterial drugs (penicillins, cephalosporins, carbapenems, and monobactams), and of the β-lactamase enzymes that destroy these drugs and help to render bacterial pathogens resistant to them. Fluorescence polarization and anisotropy-based methods for quantitation of β-lactam drugs are also reviewed. A particular emphasis is on methods for quantitative measurement of the interactions of β-lactams and other inhibitors with PBPs and β-lactamases.

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“…The importance of this loop was confirmed in RNA interference experiments that show similar phenotypes for sensor loop mutants and ATP binding site mutants. This sensor loop lies near the N and C termini, which are also suggested to be involved in protein folding in GroEL and the thermosomes [56,76,[107][108][109].…”

Section: The Substrate Recognition Mechanismmentioning

confidence: 99%

Dynamics, flexibility, and allostery in molecular chaperonins

et al. 2015

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a b s t r a c tThe chaperonins are a family of molecular chaperones present in all three kingdoms of life. They are classified into Group I and Group II. Group I consists of the bacterial variants (GroEL) and the eukaryotic ones from mitochondria and chloroplasts (Hsp60), while Group II consists of the archaeal (thermosomes) and eukaryotic cytosolic variants (CCT or TRiC). Both groups assemble into a dual ring structure, with each ring providing a protective folding chamber for nascent and denatured proteins. Their functional cycle is powered by ATP binding and hydrolysis, which drives a series of structural rearrangements that enable encapsulation and subsequent release of the substrate protein.Chaperonins have elaborate allosteric mechanisms to regulate their functional cycle. Long-range negative cooperativity between the two rings ensures alternation of the folding chambers. Positive intra-ring cooperativity, which facilitates concerted conformational transitions within the protein subunits of one ring, has only been demonstrated for Group I chaperonins. In this review, we describe our present understanding of the underlying mechanisms and the structurefunction relationships in these complex protein systems with a particular focus on the structural dynamics, allostery, and associated conformational rearrangements.

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Small molecule inhibition of a Group II chaperonin: Pinpointing a loop region within the equatorial domain as necessary for protein refolding

Cited by 6 publications

References 39 publications

The Chemical Biology of Molecular Chaperones—Implications for Modulation of Proteostasis

The Chemical Biology of Molecular Chaperones—Implications for Modulation of Proteostasis

Investigation ofβ-lactam antibacterial drugs,β-lactamases, and penicillin-binding proteins with fluorescence polarization and anisotropy: a review

Dynamics, flexibility, and allostery in molecular chaperonins

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