Crystal Structures of Pseudomonas aeruginosa GIM-1: Active-Site Plasticity in Metallo-beta-Lactamases
ForfatterBorra, Naga Pardha Saradhi; Samuelsen, Ørjan; Spencer, James; Walsh, Timothy R.; Lorentzen, marit sjo; Leiros, Hanna-Kirsti S.
Metallo- -lactamases (MBLs) have rapidly disseminated worldwide among clinically important Gram-negative bacteria and have challenged the therapeutic use of -lactam antibiotics, particularly carbapenems. The blaGIM-1 gene, encoding one such enzyme, was first discovered in a Pseudomonas aeruginosa isolate from 2002 and has more recently been reported in Enterobacteriaceae. Here, we present crystal structures of GIM-1 in the apo-zinc (metal-free), mono-zinc (where Cys221 was found to be oxidized), and di-zinc forms, providing nine independently refined views of the enzyme. GIM-1 is distinguished from related MBLs in possessing a narrower active-site groove defined by aromatic side chains (Trp228 and Tyr233) at positions normally occupied by hydrophilic residues in other MBLs. Our structures reveal considerable flexibility in two loops (loop 1, residues 60 to 66; loop 2, residues 223 to 242) adjacent to the active site, with open and closed conformations defined by alternative hydrogen- bonding patterns involving Trp228. We suggest that this capacity for rearrangement permits GIM-1 to hydrolyze a wide range of -lactams in spite of possessing a more constrained active site. Our results highlight the structural diversity within the MBL enzyme family.
ForlagAmerican Society for Microbiology
SiteringAntimicrobial Agents and Chemotherapy 57(2013) nr. 2 s. 848-854
Følgende lisensfil er knyttet til denne innførselen:
Viser innførsler relatert til tittel, forfatter og emneord.
Prognostic Impacts of Angiopoietins in NSCLC Tumor Cells and Stroma : VEGF-A Impact Is Strongly Associated with Ang-2 Andersen, Sigve; Dønnem, Tom; Al-Shibli, Khalid Ibrahim; Al-Saad, Samer; Stenvold, Helge; Busund, Lill-Tove; Bremnes, Roy M. (Journal article; Tidsskriftartikkel; Peer reviewed, 2011)Angiopoietins and their receptor Tie-2 are, in concert with VEGF-A, key mediators in angiogenesis. This study evaluates the prognostic impact of all known human angiopoietins (Ang-1, Ang-2 and Ang-4) and their receptor Tie-2, as well as their relation to the prognostic expression of VEGF-A. 335 unselected stage I-IIIA NSCLC-patients were included and tissue samples of respective tumor cells and ...
Humant papillomavirus : en litteraturstudie om HPV, dets relasjon til cancer og tiltak mot videre spredning av virus Gabrielsen, Endre (Master thesis; Mastergradsoppgave, 2012-06-01)I 1983 oppdaget zur Hausen sammenhengen mellom Humant Papillomavirus (HPV) og livmorhalskreft. På denne tiden visste man ikke at det var HPV som var årsaken til at Helaceller kunne leve in vitro. Ny forskning relaterer HPV til en rekke andre cancertyper. En stor andel anal-, oropharyngeal-, penis-, vaginal-, og vulvacancer skyldes HPV. Det er også påvist HPV i tumorvev fra øsofagus, larynx, lunge, ...
Cardiovascular adaptation in pregnancy - Effects of angiotensin II, transverse aorta constriction and high-intensity interval training on pregnant rats Songstad, Nils Thomas (Doctoral thesis; Doktorgradsavhandling, 2014-09-18)Objectives: To investigate how cardiac function, remodeling and gene expression are affected in pregnancy in response to cardiovascular stress, to detect possible adverse effects on the fetus, and to evaluate if coronary endothelial function is influenced by pregnancy and increased cardiac afterload. Methods: Pregnant and non-pregnant rats were subjected to chronic AngII-infusion, transverse aortic ...