Gating interactions steer loop conformational changes in the active site of the L1 metallo-ß-lactamase.

ß-Lactam antibiotics are the most important and widely used antibacterial agents across the world. However, the widespread dissemination of ß-lactamases among pathogenic bacteria limits the efficacy of ß-lactam antibiotics. This has created a major public health crisis. The use of ß-lactamase inhibitors has proven useful in restoring the activity of ß-lactam antibiotics, yet, effective clinically approved inhibitors against class B metallo-ß-lactamases are not available. L1, a class B3 enzyme expressed by Stenotrophomonas maltophilia, is a significant contributor to the ß-lactam resistance displayed by this opportunistic pathogen. Structurally, L1 is a tetramer with two elongated loops, α3-ß7 and ß12-α5, present around the active site of each monomer. Residues in these two loops influence substrate/inhibitor binding. To study how the conformational changes of the elongated loops affect the active site in each monomer, enhanced sampling molecular dynamics simulations were performed, Markov State Models were built, and convolutional variational autoencoder-based deep learning was applied. The key identified residues (D150a, H151, P225, Y227, and R236) were mutated and the activity of the generated L1 variants was evaluated in cell-based experiments. The results demonstrate that there are extremely significant gating interactions between α3-ß7 and ß12-α5 loops. Taken together, the gating interactions with the conformational changes of the key residues play an important role in the structural remodeling of the active site. These observations offer insights into the potential for novel drug development exploiting these gating interactions.

Neurocognitive impairment on motor imagery associated with positive symptoms in patients with first-episode schizophrenia: evidence from event-related brain potentials.

Motor imagery provides direct insight into an anatomically interconnected system involved in the integration of sensory information with motor actions, a process that is associated with positive symptoms in schizophrenia (SCZ). However, very little is known about the electrophysiological processing of motor imagery in first episode SCZ. In the current study, we used a visual hand mental rotation (MR) paradigm to manipulate the processing of motor imagery while event-related brain potentials (ERPs) were recorded in 42 SCZ participants and 40 healthy controls (HC). The 400-600 ms window was measured and analyzed for peak latencies and amplitudes. Participants with SCZ had slower reaction time (RT) and made more errors than did HC participants. Moreover, SCZ participants had lower amplitudes in the 400-600 ms window and the typical MR function for amplitudes of MR was lacking. Interestingly, the scalp activity maps for MR in SCZ exhibited an absence of activation in the left parietal site as shown in HC. Furthermore, deficits of amplitude for MR were positively correlated with positive symptom scores in SCZ. These results provide novel evidence for relationships between the electrophysiological processing of motor imagery and positive symptoms in SCZ. They further suggest that the impaired information processing of motor imagery indexed by amplitudes and specific topographic characteristics of the EEG during MR tasks may be a potentially useful and early defining biomarker for SCZ.