A structural comparison of the ppLAP-bestatin complex with inhibitor-bound complexes of bovine lens LAP, along with substrate modelling, gave clear and new insights into its substrate specificity and high level of enantioselectivity.
At pH 5.2, the active site of ppLAP is highly disordered and the two metal ions are absent, most probably due to full protonation of one of the metal-interacting residues, Lys267, explaining why ppLAP is inactive at low pH. Moreover, it was shown that Mn(2+) has a significant activation effect when bound to site 1 of ppLAP. By using a metal-dependent activity assay it was shown that site 1 in heterologously expressed ppLAP is occupied mainly by Mn(2+). At pH 9.5, the active site contains two metal ions, one identified as Mn(2+) or Zn(2+) (site 1), and the other as Zn(2+) (site 2). Crystal structures of native ppLAP at pH 9.5 and pH 5.2, and in complex with the inhibitor bestatin, show that the overall folding and hexameric organization of ppLAP are very similar to those of the closely related di-zinc leucine aminopeptidases (LAPs) from bovine lens and Escherichia coli. To provide a better understanding of its structure-function relationships, the enzyme was studied by X-ray crystallography. The zinc-dependent leucine aminopeptidase from Pseudomonas putida (ppLAP) is an important enzyme for the industrial production of enantiomerically pure amino acids. Polymer: 1 Type: polypeptide(L) Length: 497Ĭitation: Crystal structure of the leucine aminopeptidase from Pseudomonas putida reveals the molecular basis for its enantioselectivity and broad substrate specificity. Kale, A., Dijkstra, B.W., Sonke, T., Thunnissen, A.M.W.H.Įxperiment: X-RAY DIFFRACTION with resolution of 1.50 Å aeruginosa PBP3 and open avenues for future design of inhibitors of this class of PBPs. Taken together, these structural, biochemical, and computational studies provide a molecular basis for recognition of P. Energetic analysis of tightly and loosely held computed hydration sites indicates protein desolvation effects contribute significantly to PBP3 binding, and analysis of hydration site energies allows rank ordering of the second-order acylation rate constants. This is also the first example of a siderophore-conjugated triazolone-linked monocarbam complexed with any PBP. Importantly, we have identified a novel conformation that is distinct to the high-molecular-weight class B PBP subfamily, which is identifiable by common features such as a hydrophobic aromatic wall formed by Tyr503, Tyr532, and Phe533 and the structural flexibility of Tyr409 flanked by two glycine residues.
The structure of MC-1, a new siderophore-conjugated monocarbam complexed with PBP3 provides molecular insights for lead optimization. aeruginosa PBP3 is due to a distinct hydrophobic aromatic wall composed of Tyr503, Tyr532, and Phe533 interacting with the gem-dimethyl group.
The well-known affinity of the monobactam aztreonam for P. These structures reveal a conformational rearrangement of Tyr532 and Phe533 and a ligand-induced conformational change of Tyr409 and Arg489. aeruginosa PBP3 with both novel and marketed ?-lactams. Here we disclose the first high resolution cocrystal structures of the P. Penicillin-binding protein PBP3, a key therapeutic target, is an essential enzyme responsible for the final steps of peptidoglycan synthesis and is covalently inactivated by ?-lactam antibiotics. Pseudomonas aeruginosa is an opportunistic Gram-negative pathogen that causes nosocomial infections for which there are limited treatment options.
SMILES is generally considered to have the advantage of being slightly more human-readable than InChI it also has a wide base of software support with extensive theoretical (e.g., graph theory) backing. In July 2006, the IUPAC introduced the InChI as a standard for formula representation.
Other 'linear' notations include the Wiswesser Line Notation (WLN), ROSDAL and SLN (Tripos Inc). In 2007, an open standard called "OpenSMILES" was developed by the Blue Obelisk open-source chemistry community. It has since been modified and extended by others, most notably by Daylight Chemical Information Systems Inc. The original SMILES specification was developed by Arthur Weininger and David Weininger in the late 1980s.
SMILES strings can be imported by most molecule editors for conversion back into two-dimensional drawings or three-dimensional models of the molecules. The simplified molecular input line entry specification or SMILES is a specification for unambiguously describing the structure of chemical molecules using short ASCII strings.