7bj9

Structure of Sfh-I with 2-Mercaptomethyl-thiazolidine L-anti-1a

spinqualitylabelsall models 7bj9, resolution 1.21Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7bj9 is a 2 chain structure with sequence from Serratia fonticola. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.2100059Å Ligands: GOL, TWW, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q9RMI1_SERFO Publication Abstract from PubMed Metallo-beta-lactamase (MBL) production in Gram-negative bacteria is an important contributor to beta-lactam antibiotic resistance. Combining beta-lactams with beta-lactamase inhibitors (BLIs) is a validated route to overcoming resistance, but MBL inhibitors are not available in the clinic. On the basis of zinc utilization and sequence, MBLs are divided into three subclasses, B1, B2, and B3, whose differing active-site architectures hinder development of BLIs capable of "cross-class" MBL inhibition. We previously described 2-mercaptomethyl thiazolidines (MMTZs) as B1 MBL inhibitors (e.g., NDM-1) and here show that inhibition extends to the clinically relevant B2 (Sfh-I) and B3 (L1) enzymes. MMTZs inhibit purified MBLs in vitro (e.g., Sfh-I, Ki 0.16 muM) and potentiate beta-lactam activity against producer strains. X-ray crystallography reveals that inhibition involves direct interaction of the MMTZ thiol with the mono- or dizinc centers of Sfh-I/L1, respectively. This is further enhanced by sulfur-pi interactions with a conserved active site tryptophan. Computational studies reveal that the stereochemistry at chiral centers is critical, showing less potent MMTZ stereoisomers (up to 800-fold) as unable to replicate sulfur-pi interactions in Sfh-I, largely through steric constraints in a compact active site. Furthermore, in silico replacement of the thiazolidine sulfur with oxygen (forming an oxazolidine) resulted in less favorable aromatic interactions with B2 MBLs, though the effect is less than that previously observed for the subclass B1 enzyme NDM-1. In the B3 enzyme L1, these effects are offset by additional MMTZ interactions with the protein main chain. MMTZs can therefore inhibit all MBL classes by maintaining conserved binding modes through different routes. 2-Mercaptomethyl Thiazolidines (MMTZs) Inhibit All Metallo-beta-Lactamase Classes by Maintaining a Conserved Binding Mode.,Hinchliffe P, Moreno DM, Rossi MA, Mojica MF, Martinez V, Villamil V, Spellberg B, Drusano GL, Banchio C, Mahler G, Bonomo RA, Vila AJ, Spencer J ACS Infect Dis. 2021 Aug 6. doi: 10.1021/acsinfecdis.1c00194. PMID:34355567 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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