Structural insights into the substrate binding sites of O-carbamoyltransferase VtdB from Streptomyces sp. NO1W98.

The O-carbamoyltransferase VtdB catalyzes the carbamoylation of venturicidin B, which is essential for the biosynthesis of the antibiotic venturicidin A. Here, the crystal structures of VtdB and VtdB in complex with the intermediate carbamoyladenylate (VtdBCAO) were determined at resolutions of 2.99 Å and 2.90 Å, respectively. The structures resemble the conserved YrdC-like and specific Kae1-like domains. A magnesium ion and the intermediate carbamoyladenylate were also observed in the Kae1-like domain of VtdB. The structure of VtdBCAO in complex with the substrate venturicidin B was modeled by a molecular docking method to better understand the substrate binding mode, revealing a novel venturicidin B binding pocket.

A new triarylindanone and a new isobenzofuranone derivative from Selaginella tamariscina.

A new triarylindanone, namely selagindanone A (1), and a new isobenzofuranone (2), 3,4-bis(4-hydroxyphenyl)isobenzofuran-1(3H)-one, were isolated from Selaginella tamariscina. Their structures were elucidated by comprehensive spectroscopic and mass spectrometric analyses, including 1 D-, 2 D-NMR and HR-ESI-MS. Compound 1 possesses a unique structural feature of triaryl-substituted in the skeleton of 1-indanone. In addition, compound 2 showed weak cytotoxicity against human hepatocellular carcinoma SMMC-7721 and HepG2 cell lines.

Latency modulation of collicular neurons induced by electric stimulation of the auditory cortex in Hipposideros pratti: In vivo intracellular recording.

In the auditory pathway, the inferior colliculus (IC) receives and integrates excitatory and inhibitory inputs from the lower auditory nuclei, contralateral IC, and auditory cortex (AC), and then uploads these inputs to the thalamus and cortex. Meanwhile, the AC modulates the sound signal processing of IC neurons, including their latency (i.e., first-spike latency). Excitatory and inhibitory corticofugal projections to the IC may shorten and prolong the latency of IC neurons, respectively. However, the synaptic mechanisms underlying the corticofugal latency modulation of IC neurons remain unclear. Thus, this study probed these mechanisms via in vivo intracellular recording and acoustic and focal electric stimulation. The AC latency modulation of IC neurons is possibly mediated by pre-spike depolarization duration, pre-spike hyperpolarization duration, and spike onset time. This study suggests an effective strategy for the timing sequence determination of auditory information uploaded to the thalamus and cortex.

Structure-based optimization of salt-bridge network across the complex interface of PTPN4 PDZ domain with its peptide ligands in neuroglioma.

The PTP non-receptor type 4 (PTPN4) is an important regulator protein in learning, spatial memory and cerebellar synaptic plasticity; targeting the PDZ domain of PTPN4 has become as attractive therapeutic strategy for human neuroglioma. Here, we systematically examined the complex crystal structures of PTPN4 PDZ domain with its known peptide ligands; a number of charged amino acid residues were identified in these ligands and in the peptide-binding pocket of PDZ domain, which can constitute a complicated salt-bridge network across the complex interface. Molecular dynamics (MD) simulations, binding free energy calculations and continuum model analysis revealed that the electrostatic effect plays a predominant role in domain-peptide binding, while other noncovalent interactions such as hydrogen bonds and hydrophobic forces are also responsible for the binding. The computational findings were then used to guide structure-based optimization of the interfacial salt-bridge network. Consequently, five peptides were rationally designed using the high-affinity binder Cyto8-RETEV (RETEV-COOH) as template, including four single-point mutants (i.e. Cyto8-mtxe0: RETEE-COOH, Cyto8-mtxd-1: RETDV-COOH, Cyto8-mtxd-3: RDTEV-COOH and Cyto8-mtxk-4: KETEV-COOH) and one double-point mutant (i.e. Cyto8-mtxd-1k-4: KETDV-COOH). Binding assays confirmed that three (Cyto8-mtxd-1, Cyto8-mtxk-4 and Cyto8-mtxd-1k-4) out of the five designed peptides exhibit moderately or considerably increased affinity as compared to the native peptide Cyto8-RETEV.