Generation and evaluation of dimension-reduced amino acid parameter representations by artificial neural networks

Meiler, Jens; Müller, Michael; Zeidler, Anita; Schmäschke, Felix

doi:10.1007/s008940100038

Cited by 254 publications

(203 citation statements)

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“…S2 and Table S2). It is conceivable that alanine, which has a high helix propensity (50,51), disrupts the ␤ hairpin loop structure and induces formation of a small ␣ helix in L3. Thermal denaturation was monitored by CD analysis (see Fig.…”

Section: Resultsmentioning

confidence: 99%

Elucidating the Role of Residue 67 in IMP-Type Metallo-β-Lactamase Evolution

LaCuran

Pegg

Liu

et al. 2015

Antimicrob Agents Chemother

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f Antibiotic resistance in bacteria is ever changing and adapting, as once-novel ␤-lactam antibiotics are losing their efficacy, primarily due to the production of ␤-lactamases. Metallo-␤-lactamases (MBLs) efficiently inactivate a broad range of ␤-lactam antibiotics, including carbapenems, and are often coexpressed with other antibacterial resistance factors. The rapid dissemination of MBLs and lack of novel antibacterials pose an imminent threat to global health. In an effort to better counter these resistanceconferring ␤-lactamases, an investigation of their natural evolution and resulting substrate specificity was employed. In this study, we elucidated the effects of different amino acid substitutions at position 67 in IMP-type MBLs on the ability to hydrolyze and confer resistance to a range of ␤-lactam antibiotics. Wild-type ␤-lactamases IMP-1 and IMP-10 and mutants IMP-1-V67A and IMP-1-V67I were characterized biophysically and biochemically, and MICs for Escherichia coli cells expressing these enzymes were determined. We found that all variants exhibited catalytic efficiencies (k cat /K m ) equal to or higher than that of IMP-1 against all tested ␤-lactams except penicillins, against which IMP-1 and IMP-1-V67I showed the highest k cat /K m values. The substrate-specific effects of the different amino acid substitutions at position 67 are discussed in light of their side chain structures and possible interactions with the substrates. Docking calculations were employed to investigate interactions between different side chains and an inhibitor used as a ␤-lactam surrogate. The differences in binding affinities determined experimentally and computationally seem to be governed by hydrophobic interactions between residue 67 and the inhibitor and, by inference, the ␤-lactam substrates.

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Section: Resultsmentioning

confidence: 99%

Elucidating the Role of Residue 67 in IMP-Type Metallo-β-Lactamase Evolution

LaCuran

Pegg

Liu

et al. 2015

Antimicrob Agents Chemother

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“…By default, three separate programs, Psipred, 22 SAM-T99, 23 and JUFO, 24 are used by standard Rosetta to predict secondary structure (Supporting Information Fig. S1), which guides the standard Rosetta fragment selection process.…”

Section: Resultsmentioning

confidence: 99%

De novo structure generation using chemical shifts for proteins with high‐sequence identity but different folds

Shen

Bryan

et al. 2010

Protein Science

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Proteins with high-sequence identity but very different folds present a special challenge to sequence-based protein structure prediction methods. In particular, a 56-residue three-helical bundle protein (GA 95 ) and an a/b-fold protein (GB 95 ), which share 95% sequence identity, were targets in the CASP-8 structure prediction contest. With only 12 out of 300 submitted server-CASP8 models for GA 95

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“…Structure predictions of Munc13 peptideCaM complexes were performed as described previously (14). Briefly, the structures of the Munc13 peptides were modeled using the PepFold program (29) on the basis of secondary-structure predictions from JuFo (31) and PSIPRED (30). Structures of different peptide-CaM complexes (Protein Data Bank [PDB] entries 1CDL, 1CKK, 1QS7, 1QTX, 1WRZ, 2BBM, 2F3Y, and 2O60) were used as a starting point for fast global protein docking searches with the PatchDock server (18), thereby accounting for the broad variety of CaM-binding modes (from parallel to antiparallel) and conformations (from open to highly compact).…”

Section: Methodsmentioning

confidence: 99%

Nonconserved Ca²⁺/Calmodulin Binding Sites in Munc13s Differentially Control Synaptic Short-Term Plasticity

Lipstein

Schaks

Dimova

et al. 2012

Molecular and Cellular Biology

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f Munc13s are presynaptic proteins that mediate synaptic vesicle priming and thereby control the size of the readily releasable pool of vesicles. During high synaptic activity, Munc13-1 and its closely related homolog, ubMunc13-2, bind Ca 2؉ /calmodulin, resulting in enhanced priming activity and in changes of short-term synaptic plasticity characteristics. Here, we studied whether bMunc13-2 and Munc13-3, two remote isoforms of Munc13-1 with a neuronal subtype-specific expression pattern, mediate synaptic vesicle priming and regulate short-term synaptic plasticity in a Ca 2؉ /calmodulin-dependent manner. We identified a single functional Ca 2؉ /calmodulin binding site in these isoforms and provide structural evidence that all Munc13s employ a common mode of interaction with calmodulin despite the lack of sequence homology between their Ca 2؉ /calmodulin binding sites. Electrophysiological analysis showed that, during high-frequency activity, Ca 2؉ /calmodulin binding positively regulates the priming activity of bMunc13-2 and Munc13-3, resulting in an increase in the size of the readily releasable pool of vesicles and subsequently in strong short-term synaptic enhancement of neurotransmission. We conclude that Ca 2؉ /calmodulin-dependent regulation of priming activity is structurally and functionally conserved in all Munc13 proteins, and that the composition of Munc13 isoforms in a neuron differentially controls its short-term synaptic plasticity characteristics.

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Generation and evaluation of dimension-reduced amino acid parameter representations by artificial neural networks

Cited by 254 publications

References 1 publication

Elucidating the Role of Residue 67 in IMP-Type Metallo-β-Lactamase Evolution

Elucidating the Role of Residue 67 in IMP-Type Metallo-β-Lactamase Evolution

De novo structure generation using chemical shifts for proteins with high‐sequence identity but different folds

Nonconserved Ca²⁺/Calmodulin Binding Sites in Munc13s Differentially Control Synaptic Short-Term Plasticity

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Generation and evaluation of dimension-reduced amino acid parameter representations by artificial neural networks

Cited by 254 publications

References 1 publication

Elucidating the Role of Residue 67 in IMP-Type Metallo-β-Lactamase Evolution

Elucidating the Role of Residue 67 in IMP-Type Metallo-β-Lactamase Evolution

De novo structure generation using chemical shifts for proteins with high‐sequence identity but different folds

Nonconserved Ca2+/Calmodulin Binding Sites in Munc13s Differentially Control Synaptic Short-Term Plasticity

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Nonconserved Ca²⁺/Calmodulin Binding Sites in Munc13s Differentially Control Synaptic Short-Term Plasticity