Leptomycins A and B, new antifungal antibiotics. I. Taxonomy of the producing strain and their fermentation, purification and characterization.

Hamamoto, Toshiro; Gunji, Shigemichi; Tsuji, Hiroaki; Beppu, Teruhiko

doi:10.7164/antibiotics.36.639

Cited by 149 publications

(76 citation statements)

References 15 publications

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“…The substrate repertoire of each Kapβ and the functional consequences of pathway specificities are some of the main challenges in understanding intracellular signaling and trafficking. In the case of nuclear export, Crm1 inhibitor leptomycin B has been crucial for identifying many Crm1 substrates 3,4 . Such specific inhibitors of nuclear import could be invaluable for proteomic analyses to map extensive nuclear traffic, but none has been found.…”

Section: Introductionmentioning

confidence: 99%

“…R.m.s. deviations for all Pro-Tyr atoms and for arginine guanido group atoms in the R/H/Kx (2)(3)(4)(5) PY motifs are 0.9Å and 1.2Å, respectively, upon Kapβ2 superposition. At the N-terminal motifs, hnRNP M residues 51-54 in the basic 50-KEKNIKR-56 motif and hnRNP A1 residues 274-277 in the hydrophobic motif also overlap (main chain r.m.s.…”

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confidence: 96%

“…deviation 1.3Å). In contrast, intervening segments 61-FE-62 in hnRNP M and 285-SSG-287 in hnRNP A1, and those between the Nterminal and R/H/Kx (2)(3)(4)(5) PY motifs, diverge up to 4.0Å and 7.2Å, respectively (Fig. 1b).…”

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confidence: 97%

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AbstractKapβ2 (also called transportin) recognizes PY nuclear localization signal (NLS), a new class of NLS with a R/H/Kx (2)(3)(4)(5) PY motif. Here we show that Kapβ2 complexes containing hydrophobic and basic PY-NLSs, as classified by the composition of an additional N-terminal motif, converge in structure only at consensus motifs, which explains ligand diversity.

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confidence: 99%

“…1b). Thus, the NLSs converge structurally at three sites: the N-terminal motif and the arginine and proline-tyrosine residues of the R/H/Kx (2)(3)(4)(5) PY motif. These sites are key binding epitopes, confirming their designation as consensus sequences, and the structurally variable linkers vary in both sequence and length across the PY-NLS family.…”

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confidence: 99%

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Structure-based design of a pathway-specific nuclear import inhibitor

Cansizoglu

Lee

Zhang

et al. 2007

Nat Struct Mol Biol

152

245

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Kapβ2 (also called transportin) recognizes PY nuclear localization signal (NLS), a new class of NLS with a R/H/Kx (2)(3)(4)(5) PY motif. Here we show that Kapβ2 complexes containing hydrophobic and basic PY-NLSs, as classified by the composition of an additional N-terminal motif, converge in structure only at consensus motifs, which explains ligand diversity. On the basis of these data and complementary biochemical analyses, we designed a Kapβ2-specific nuclear import inhibitor, M9M.Ten different import karyopherin-βs (Kapβs, also called importin-βs) 1 mediate trafficking of human proteins into the cell nucleus through recognition of distinct NLSs. Large panels of import substrates are known only for Kapβ1 (importin-β) and Kapβ2 (transportin) 1,2 . The substrate repertoire of each Kapβ and the functional consequences of pathway specificities are some of the main challenges in understanding intracellular signaling and trafficking. In the case of nuclear export, Crm1 inhibitor leptomycin B has been crucial for identifying many Crm1 substrates 3,4 . Such specific inhibitors of nuclear import could be invaluable for proteomic analyses to map extensive nuclear traffic, but none has been found. Two classes of NLS are currently known: short, basic classical NLSs that bind the heterodimer 5), and newly identified PY-NLSs that bind Kapβ2 (ref.2). PY-NLSs are 20-to 30-residue signals with intrinsic structural disorder, overall basic character, C-terminal R/K/Hx 2-5 PY motifs (where x 2-5 is any sequence of 2-5 residues) and N-terminal hydrophobic or basic motifs. These weak but orthogonal characteristics have provided substantial limits in sequence space, enabling the identification of over 100 PY-NLS-containing human proteins 2 . Two subclasses, hPY-NLSs and bPY-NLSs, are defined by their N-terminal motifs: hPY-NLSs contain ϕG/A/Sϕϕ motifs (where ϕ is a hydrophobic residue), whereas bPY-NLSs are enriched with basic residues.We have previously solved the structure of human Kapβ2 bound to the hPY-NLS of heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) 2 . Here we have solved the 3.1-Å Fig. 1a,b; Kapβ2 435-780 Cα r.m.s. deviation is 0.9Å). Their NLS termini are structurally diverse, consistent with their apparent lack of sequence conservation 2 . At the N terminus, hnRNP A1 residues 263-266 bind the convex side of Kapβ2 (ref.2), whereas the N terminus of hnRNP M proceeds toward the Kapβ2 arch opening. At the C terminus, hnRNP A1 is disordered beyond Pro288-Tyr289, whereas hnRNP M extends 5 residues beyond its Pro-Tyr motif.Residues 51-64 of hnRNP M and residues 273-289 of hnRNP A1 contact a common Kapβ2 surface, with the highest overlap at their Pro-Tyr motifs (Fig. 1b). R.m.s. deviations for all Pro-Tyr atoms and for arginine guanido group atoms in the R/H/Kx (2-5) PY motifs are 0.9Å and 1.2Å, respectively, upon Kapβ2 superposition. At the N-terminal motifs, hnRNP M residues 51-54 in the basic 50-KEKNIKR-56 motif and hnRNP A1 residues 274-277 in the hydrophobic motif also overlap (main chain r.m.s. deviation ...

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Section: Introductionmentioning

confidence: 99%

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confidence: 96%

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confidence: 97%

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confidence: 99%

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confidence: 99%

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Structure-based design of a pathway-specific nuclear import inhibitor

Cansizoglu

Lee

Zhang

et al. 2007

Nat Struct Mol Biol

152

245

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Chemical Genomics Based on Yeast Genetics

Nishimura

Yashiroda

Yoshida

2009

Protein Targeting With Small Molecules

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Proteinreaktive Naturstoffe

2005

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In der Post‐Genom‐Ära steht man vor der gewaltigen Aufgabe, die Strukturen und Funktionen zehntausender codierter Proteine zuzuweisen. Zur Analyse der Proteinfunktion werden neue Technologien mit großer Bandbreite entwickelt, etwa die aktivitätsbasierte Proteinanalyse (activity‐based protein profiling, ABPP). Bei diesem Verfahren sollen auf das aktive Zentrum gerichtete chemische Sonden entwickelt werden, um die Enzyme in ganzen Proteomen zu analysieren. Derartige chemische Proteomtechnologien können von proteinreaktiven Naturstoffen lernen, die Enzyme der unterschiedlichsten Klassen durch ein bemerkenswert vielfältiges Spektrum an Mechanismen kovalent modifizieren und somit eine reiche Quelle an Konzepten für die Entwicklung gegen aktive Zentren gerichteter Proteomsonden bilden. Hier werden wir anhand unterschiedlicher Naturstoffe zeigen, wie ihre Wirkmechanismen zum Fortschritt chemischer Proteomtechnologien wie ABPP beigetragen haben.

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Leptomycins A and B, new antifungal antibiotics. I. Taxonomy of the producing strain and their fermentation, purification and characterization.

Cited by 149 publications

References 15 publications

Structure-based design of a pathway-specific nuclear import inhibitor

Structure-based design of a pathway-specific nuclear import inhibitor

Chemical Genomics Based on Yeast Genetics

Proteinreaktive Naturstoffe

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