3D4F

SHV-1 beta-lactamase complex with LN1-255

Summary for 3D4F

• Entry DOI: 10.2210/pdb3d4f/pdb
• Related: 1GA0 1SHV
• Descriptor: Beta-lactamase SHV-1, CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE, (3R)-4-{[(3,4-dihydroxyphenyl)acetyl]oxy}-N-(2-formylindolizin-3-yl)-3-sulfino-D-valine, ... (4 entities in total)
• Functional Keywords: beta-lactamase inhibitor, drug design, antibiotic resistance, hydrolase, plasmid
• Biological source: Klebsiella pneumoniae
• Total number of polymer chains: 1
• Total formula weight: 32767.67

Authors

Pattanaik, P.,Bethel, C.R.,Hujer, A.M.,Bonomo, R.A.,Buynak, J.D.,van den Akker, F. (deposition date: 2008-05-14, release date: 2009-02-10, Last modification date: 2024-10-09)

Primary citation

Pattanaik, P.,Bethel, C.R.,Hujer, A.M.,Hujer, K.M.,Distler, A.M.,Taracila, M.,Anderson, V.E.,Fritsche, T.R.,Jones, R.N.,Pagadala, S.R.,van den Akker, F.,Buynak, J.D.,Bonomo, R.A.
Strategic Design of an Effective {beta}-Lactamase Inhibitor: LN-1-255, A 6-ALKYLIDENE-2'-SUBSTITUTED PENICILLIN SULFONE
J.Biol.Chem., 284:945-953, 2009

PubMed Abstract: In an effort to devise strategies for overcoming bacterial beta-lactamases, we studied LN-1-255, a 6-alkylidene-2'-substituted penicillin sulfone inhibitor. By possessing a catecholic functionality that resembles a natural bacterial siderophore, LN-1-255 is unique among beta-lactamase inhibitors. LN-1-255 combined with piperacillin was more potent against Escherichia coli DH10B strains bearing bla(SHV) extended-spectrum and inhibitor-resistant beta-lactamases than an equivalent amount of tazobactam and piperacillin. In addition, LN-1-255 significantly enhanced the activity of ceftazidime and cefpirome against extended-spectrum cephalosporin and Sme-1 containing carbapenem-resistant clinical strains. LN-1-255 inhibited SHV-1 and SHV-2 beta-lactamases with nm affinity (K(I) = 110 +/- 10 and 100 +/- 10 nm, respectively). When LN-1-255 inactivated SHV beta-lactamases, a single intermediate was detected by mass spectrometry. The crystal structure of LN-1-255 in complex with SHV-1 was determined at 1.55A resolution. Interestingly, this novel inhibitor forms a bicyclic aromatic intermediate with its carbonyl oxygen pointing out of the oxyanion hole and forming hydrogen bonds with Lys-234 and Ser-130 in the active site. Electron density for the "tail" of LN-1-255 is less ordered and modeled in two conformations. Both conformations have the LN-1-255 carboxyl group interacting with Arg-244, yet the remaining tails of the two conformations diverge. The observed presence of the bicyclic aromatic intermediate with its carbonyl oxygen positioned outside of the oxyanion hole provides a rationale for the stability of this inhibitory intermediate. The 2'-substituted penicillin sulfone, LN-1-255, is proving to be an important lead compound for novel beta-lactamase inhibitor design.

PubMed: 18955486
DOI: 10.1074/jbc.M806833200

Experimental method

X-RAY DIFFRACTION (1.55 Å)