Antimicrobial resistance is one of the most urgent global health threats, especially in the post-pandemic era. Antimicrobial peptides (AMPs) offer a promising alternative to traditional antibiotics, driving growing interest in recent years. dbAMP is a comprehensive database offering extensive annotations on AMPs, including sequence information, functional activity data, physicochemical properties and structural annotations. In this update, dbAMP has curated data from over 5200 publications, encompassing 33,065 AMPs and 2453 antimicrobial proteins from 3534 organisms. Additionally, dbAMP utilizes ESMFold to determine the three-dimensional structures of AMPs, providing over 30,000 structural annotations that facilitate structure-based functional insights for clinical drug development. Furthermore, dbAMP employs molecular docking techniques, providing over 100 docked complexes that contribute useful insights into the potential mechanisms of AMPs. The toxicity and stability of AMPs are critical factors in assessing their potential as clinical drugs. The updated dbAMP introduced an efficient tool for evaluating the hemolytic toxicity and half-life of AMPs, alongside an AMP optimization platform for designing AMPs with high antimicrobial activity, reduced toxicity and increased stability. The updated dbAMP is freely accessible at https://awi.cuhk.edu.cn/dbAMP/. Overall, dbAMP represents a comprehensive and essential resource for AMP analysis and design, poised to advance antimicrobial strategies in the post-pandemic era.

Radiation of the plant pyridoxal 5′-phosphate (PLP)-dependent aromaticl-amino acid decarboxylase (AAAD) family has yielded an array of paralogous enzymes exhibiting divergent substrate preferences and catalytic mechanisms. Plant AAADs catalyze either the decarboxylation or decarboxylation-dependent oxidative deamination of aromaticl-amino acids to produce aromatic monoamines or aromatic acetaldehydes, respectively. These compounds serve as key precursors for the biosynthesis of several important classes of plant natural products, including indole alkaloids, benzylisoquinoline alkaloids, hydroxycinnamic acid amides, phenylacetaldehyde-derived floral volatiles, and tyrosol derivatives. Here, we present the crystal structures of four functionally distinct plant AAAD paralogs. Through structural and functional analyses, we identify variable structural features of the substrate-binding pocket that underlie the divergent evolution of substrate selectivity toward indole, phenyl, or hydroxyphenyl amino acids in plant AAADs. Moreover, we describe two mechanistic classes of independently arising mutations in AAAD paralogs leading to the convergent evolution of the derived aldehyde synthase activity. Applying knowledge learned from this study, we successfully engineered a shortened benzylisoquinoline alkaloid pathway to produce (S)-norcoclaurine in yeast. This work highlights the pliability of the AAAD fold that allows change of substrate selectivity and access to alternative catalytic mechanisms with only a few mutations.

The resonant Auger process is studied in intense x-ray laser fields. It is shown that the dressing of the initial and decaying states by the field leads to coupled complex potential surfaces which, even for diatomic molecules, possess intersections at which the nonadiabatic couplings are singular. HCl is studied as an explicit showcase example. The exact results differ qualitatively from those without rotations. A wealth of nonadiabatic phenomena is expected in decay processes in intense x-ray fields.

Steroid hormones are essential in stress response, immune system regulation, and reproduction in mammals. Steroids with 3-oxo-Δ⁴structure, such as testosterone or progesterone, are catalyzed by steroid 5α-reductases (SRD5As) to generate their corresponding 3-oxo-5α steroids, which are essential for multiple physiological and pathological processes. SRD5A2 is already a target of clinically relevant drugs. However, the detailed mechanism of SRD5A-mediated reduction remains elusive. Here we report the crystal structure of PbSRD5A fromProteobacteria bacterium, a homolog of both SRD5A1 and SRD5A2, in complex with the cofactor NADPH at 2.0 Å resolution. PbSRD5A exists as a monomer comprised of seven transmembrane segments (TMs). The TM1-4 enclose a hydrophobic substrate binding cavity, whereas TM5-7 coordinate cofactor NADPH through extensive hydrogen bonds network. Homology-based structural models of HsSRD5A1 and -2, together with biochemical characterization, define the substrate binding pocket of SRD5As, explain the properties of disease-related mutants and provide an important framework for further understanding of the mechanism of NADPH mediated steroids 3-oxo-Δ⁴reduction. Based on these analyses, the design of therapeutic molecules targeting SRD5As with improved specificity and therapeutic efficacy would be possible.