A History of Protein Biosynthesis and Ribosome Research

Rheinberger, Hans‐Jörg

doi:10.1002/3527603433.ch1

Cited by 15 publications

(9 citation statements)

References 152 publications

(161 reference statements)

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“…As highlighted in the book chapter of Gale and coworkers, the sites of interaction of these important inhibitors required the development of cell-free in vitro translation systems using crude extracts that were competent for mRNA-directed polypeptide synthesis. These systems were first utilized in the 1960s to decipher the genetic code (reviewed by Rheinberger, 2004). Together with the subsequent development of model systems to monitor individual steps of protein synthesis, a more detailed understanding of the steps of protein synthesis inhibited by each antibiotic emerged.…”

Section: Antibiotics and Ribosome Functionmentioning

confidence: 99%

Probing Translation with Small-Molecule Inhibitors

Blanchard

Cooperman

Wilson

2010

Chemistry & Biology

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Summary The translational apparatus of the bacterial cell remains one of the principal targets of antibiotics for the clinical treatment of infection worldwide. Since the introduction of specific translation inhibitors into clinical practise in the late 1940’s, intense efforts have been made to understand their precise mechanisms of action. Such research has often revealed significant and sometimes unexpected insights into many fundamental aspects of the translation mechanism. Central to progress in this area, high-resolution crystal structures of the bacterial ribosome identifying the sites of antibiotic binding are now available, which, together with recent developments in single-molecule and fast-kinetic approaches, provide an integrated view of the dynamic translation process. Assays employing these approaches and focusing on specific steps of the overall translation process are amenable for drug-screening. Such assays, coupled with structural studies, have the potential not only to accelerate the discovery of novel and effective antimicrobial agents, but also to refine our understanding of the translation mechanism, since antibiotics often stabilize specific functional states of the ribosome and allow distinct translation steps to be dissected in molecular detail.

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Section: Antibiotics and Ribosome Functionmentioning

confidence: 99%

Probing Translation with Small-Molecule Inhibitors

Blanchard

Cooperman

Wilson

2010

Chemistry & Biology

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“…XX wieku zakładano, że obecny w tych strukturach kwas rybonukleinowy stanowi szablon, na podstawie którego aminokwasy łączą się w łańcuchy białkowe. Aby podkreślić znaczenie RNA, w 1958 roku Howard Dintzis zaproponował obowiązujący do dziś termin "rybosom", który po raz pierwszy pojawił się w publikacji Richarda Robertsa pięć lat później [50,51]. [53].…”

Section: Cząsteczka X -Mrnaunclassified

100 lat RNA. Diamentowy jubileusz informacyjnego RNA

et al. 2021

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W 2021 roku mija 100 lat od poznania kwasu rybonukleinowego oraz 60 lat od odkrycia informacyjnego (messenger) RNA i kodu genetycznego. Z okazji tego wyjątkowego jubileuszu pragniemy przypomnieć najważniejsze wydarzenia w historii kwasów nukleinowych, które doprowadziły do powyższych odkryć. Wspomniany początek nowej ery w nauce spowodowany izolacją nukleiny, a następnie kwasu rybonukleinowego, którego składniki i właściwości były stopniowo poznawane, często przez mało znanych badaczy. Wyróżnienie RNA i DNA oraz analiza ich występowania w komórkach pozwoliły sformułować pierwsze wnioski dotyczące funkcji tych molekuł. Konkluzje dotyczące proporcji zasad azotowych w DNA doprowadziły do poznania struktury podwójnej helisy, wywołując lawinę pytań o istotę przekazywania informacji genetycznej. Odpowiedzi zaczęły nasuwać się wraz z odkryciem mRNA, a poznanie pierwszej trójki nukleotydów kodującej fenyloalaninę rozpoczęło wyścig o rozszyfrowanie kodu genetycznego. Powyższe odkrycia stanowią fundament biologii molekularnej. Diamentowy jubileusz zbiegł się z opracowaniem szczepionki przeciwko SARS-CoV-2 opartej o mRNA.

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“…Studies of the mutant proinsulin syndrome ( 17 ) have built on general principles of cell biology and protein chemistry established over the past sixty years ( 26 – 28 ). This deep interdisciplinary background highlights mechanisms underlying the biosynthesis of disulfide-stabilized secretory proteins from the scale of organelles and macromolecular complexes ( 29 , 30 ) to the molecular biophysics of a nascent polypeptide chain’s conformational search ( 31 – 34 ).…”

Section: Introductionmentioning

confidence: 99%

Peptide Model of the Mutant Proinsulin Syndrome. I. Design and Clinical Correlation

et al. 2022

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The mutant proinsulin syndrome is a monogenic cause of diabetes mellitus due to toxic misfolding of insulin’s biosynthetic precursor. Also designated mutant INS-gene induced diabetes of the young (MIDY), this syndrome defines molecular determinants of foldability in the endoplasmic reticulum (ER) of β-cells. Here, we describe a peptide model of a key proinsulin folding intermediate and variants containing representative clinical mutations; the latter perturb invariant core sites in native proinsulin (LeuB15→Pro, LeuA16→Pro, and PheB24→Ser). The studies exploited a 49-residue single-chain synthetic precursor (designated DesDi), previously shown to optimize in vitro efficiency of disulfide pairing. Parent and variant peptides contain a single disulfide bridge (cystine B19-A20) to provide a model of proinsulin’s first oxidative folding intermediate. The peptides were characterized by circular dichroism and redox stability in relation to effects of the mutations on (a) in vitro foldability of the corresponding insulin analogs and (b) ER stress induced in cell culture on expression of the corresponding variant proinsulins. Striking correlations were observed between peptide biophysical properties, degree of ER stress and age of diabetes onset (neonatal or adolescent). Our findings suggest that age of onset reflects the extent to which nascent structure is destabilized in proinsulin’s putative folding nucleus. We envisage that such peptide models will enable high-resolution structural studies of key folding determinants and in turn permit molecular dissection of phenotype-genotype relationships in this monogenic diabetes syndrome. Our companion study (next article in this issue) employs two-dimensional heteronuclear NMR spectroscopy to define site-specific perturbations in the variant peptides.

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A History of Protein Biosynthesis and Ribosome Research

Cited by 15 publications

References 152 publications

Probing Translation with Small-Molecule Inhibitors

Probing Translation with Small-Molecule Inhibitors

100 lat RNA. Diamentowy jubileusz informacyjnego RNA

Peptide Model of the Mutant Proinsulin Syndrome. I. Design and Clinical Correlation

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