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Anhydromuropeptide permease (AmpG) is a transporter protein located in the inner membrane of certain gram -negative bacteria, involved in peptidoglycan (PG) recycling and β-lactamase induction. Decreased AmpG function reduces resistance of antibiotic-resistant bacteria to β-lactam antibiotics. Therefore, AmpG-targeting inhibitors are promising ‘antibiotic adjuvants’. However, as the tertiary structure of AmpG has not yet been identified, the development of targeted inhibitors remains challenging. We present four cryo-electron microscopy (cryo-EM) structures: the apo-inward and apo-outward state structures and the inward-occluded and outward states complexed with the substrate GlcNAc-1,6-anhMurNAc. Through functional analysis and molecular dynamics (MD) simulations, we identified motif A, which stabilizes the outward state, substrate-binding pocket, and protonation-related residues. Based on the structure of AmpG and our experimental results, we propose a muropeptide transport mechanism for AmpG. A deeper understanding of its structure and transport mechanism provides a foundation for the development of antibiotic adjuvants. Here, the authors present cryo-EM structures of Anhydromuropeptide permease in apo-inward, apo-outward, inward-occluded, and an outward-facing substrate, providing mechanistic insights into muropeptide translocation.

Thus far, attempts to develop drugs that target corticotropin-releasing hormone receptor 1 (CRF 1 R), a drug target in stress-related therapy, have been unsuccessful. Studies have focused on using high-resolution G protein-coupled receptor (GPCR) structures to develop drugs. X-ray free-electron lasers (XFELs), which prevent radiation damage and provide access to high-resolution compositions, have helped accelerate GPCR structural studies. We elucidated the crystal structure of CRF 1 R complexed with a BMK-I-152 antagonist at 2.75 Å using fixed-target serial femtosecond crystallography. The results revealed that two unique hydrogen bonds are present in the hydrogen bond network, the stalk region forms an alpha helix and the hydrophobic network contains an antagonist binding site. We then developed two antagonists—BMK-C203 and BMK-C205—and determined the CRF 1 R/BMK-C203 and CRF 1 R/BMK-C205 complex structures at 2.6 and 2.2 Å, respectively. BMK-C205 exerted significant antidepressant effects in mice and, thus, may be utilized to effectively identify structure-based drugs against CRF 1 R. Drug discovery: Hormone receptor structure helps search for new antidepressants Structural studies of complexes of a receptor protein for corticotropin-releasing hormone and specific small molecules could guide the development of new antidepressants and drugs for stress-related diseases. The activity of the corticotropin-releasing hormone receptor 1 protein has been associated with many human diseases, including psychiatric disorders, diabetes, cancer, osteoporosis, cardiovascular conditions and neurodegeneration. Hoyoung Kim at Yonsei University in Seoul, South Korea, utilized X-ray free electron laser technology, a method that minimizes sample damage, to determine the protein complexes. Through their study, they unveiled subtle, previously overlooked structural characteristics at two crucial sites. Leveraging these insights, they developed multiple ‘antagonist’ compounds that disrupt the protein’s normal function. One of these antagonists demonstrated significant antidepressant effects in mouse models, sparking hope for potential similar benefits in humans.