1onh
From Proteopedia
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| - | [[Image:1onh.gif|left|200px]] | + | [[Image:1onh.gif|left|200px]] |
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| - | '''GC1 beta-lactamase with a penem inhibitor''' | + | {{Structure |
| + | |PDB= 1onh |SIZE=350|CAPTION= <scene name='initialview01'>1onh</scene>, resolution 1.38Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=WY4:7-(5,6-DIHYDRO-8H-IMIDAZO[2,1-C][1,4]OXAZIN-2-YL)-6-FORMYL-2,7-DIHYDRO-+[1,4]THIAZEPINE-3-CARBOXYLIC+ACID'>WY4</scene> and <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] | ||
| + | |GENE= BLAC ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=550 Enterobacter cloacae]) | ||
| + | }} | ||
| + | |||
| + | '''GC1 beta-lactamase with a penem inhibitor''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 1ONH is a [ | + | 1ONH is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Enterobacter_cloacae Enterobacter cloacae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1ONH OCA]. |
==Reference== | ==Reference== | ||
| - | Inhibition of class A and class C beta-lactamases by penems: crystallographic structures of a novel 1,4-thiazepine intermediate., Nukaga M, Abe T, Venkatesan AM, Mansour TS, Bonomo RA, Knox JR, Biochemistry. 2003 Nov 18;42(45):13152-9. PMID:[http:// | + | Inhibition of class A and class C beta-lactamases by penems: crystallographic structures of a novel 1,4-thiazepine intermediate., Nukaga M, Abe T, Venkatesan AM, Mansour TS, Bonomo RA, Knox JR, Biochemistry. 2003 Nov 18;42(45):13152-9. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/14609325 14609325] |
[[Category: Beta-lactamase]] | [[Category: Beta-lactamase]] | ||
[[Category: Enterobacter cloacae]] | [[Category: Enterobacter cloacae]] | ||
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[[Category: mixed alpha/beta]] | [[Category: mixed alpha/beta]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Mar 20 13:13:10 2008'' |
Revision as of 11:13, 20 March 2008
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| , resolution 1.38Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Gene: | BLAC (Enterobacter cloacae) | ||||||
| Activity: | Beta-lactamase, with EC number 3.5.2.6 | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
GC1 beta-lactamase with a penem inhibitor
Overview
A new beta-lactamase inhibitor, a methylidene penem having a 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine heterocyclic substituent at the C6 position with a Z configuration, irreversibly inhibits both class A and class C serine beta-lactamases with IC(50) values of 0.4 and 9.0 nM for TEM-1 and SHV-1 (class A), respectively, and 4.8 nM in AmpC (class C) beta-lactamases. The compound also inhibits irreversibly the class C extended-spectrum GC1 beta-lactamase (IC(50) = 6.2 nM). High-resolution crystallographic structures of a reaction intermediate of (5R)-(6Z)-6-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazin-2-ylmethylene)-7-oxo -4-thia-1-azabicyclo[3.2.0]hept-2-ene-3-carboxylic acid 1 with the SHV-1 beta-lactamase and with the GC1 beta-lactamase have been determined by X-ray diffraction to resolutions of 1.10 and 1.38 A, respectively. The two complexes were refined to crystallographic R-factors (R(free)) of 0.141 (0.186) and 0.138 (0.202), respectively. Cryoquenching of the reaction of 1 with each beta-lactamase crystal produced a common, covalently bound intermediate. After acylation of the serine, a nucleophilic attack by the departing thiolate on the C6' atom yielded a novel seven-membered 1,4-thiazepine ring having R stereochemistry at the new C7 moiety. The orientation of this ring in each complex differs by a 180 degrees rotation about the bond to the acylated serine. The acyl ester bond is stabilized to hydrolysis through resonance stabilization with the dihydrothiazepine ring and by low occupancy or disorder of hydrolytic water molecules. In the class A complex, the buried water molecule on the alpha-face of the ester bond appears to be loosely bound or absent. In the class C complex, a water molecule on the beta-face is disordered and poorly activated for hydrolysis. Here, the acyl intermediate is unable to assist its own hydrolysis, as is thought to occur with many class C substrates.
About this Structure
1ONH is a Single protein structure of sequence from Enterobacter cloacae. Full crystallographic information is available from OCA.
Reference
Inhibition of class A and class C beta-lactamases by penems: crystallographic structures of a novel 1,4-thiazepine intermediate., Nukaga M, Abe T, Venkatesan AM, Mansour TS, Bonomo RA, Knox JR, Biochemistry. 2003 Nov 18;42(45):13152-9. PMID:14609325
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