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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
40
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pubmed:dateCreated |
2006-10-4
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pubmed:abstractText |
beta-Lactamases are one of the major causes of antibiotic resistance in Gram negative bacteria. The continuing evolution of beta-lactamases that are capable of hydrolyzing our most potent beta-lactams presents a vexing clinical problem, in particular since a number of them are resistant to inhibitors. The efficient inhibition of these enzymes is therefore of great clinical importance. Building upon our previous structural studies that examined tazobactam trapped as a trans-enamine intermediate in a deacylation deficient SHV variant, we designed a novel penam sulfone derivative that forms a more stable trans-enamine intermediate. We report here the 1.28 A resolution crystal structure of wt SHV-1 in complex with a rationally designed penam sulfone, SA2-13. The compound is covalently bound to the active site of wt SHV-1 similar to tazobactam yet forms an additional salt-bridge with K234 and hydrogen bonds with S130 and T235 to stabilize the trans-enamine intermediate. Kinetic measurements show that SA2-13, once reacted with SHV-1 beta-lactamase, is about 10-fold slower at being released from the enzyme compared to tazobactam. Stabilizing the trans-enamine intermediate represents a novel strategy for the rational design of mechanism-based class A beta-lactamase inhibitors.
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pubmed:grant |
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pubmed:commentsCorrections |
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-10089411,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-10231522,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-10820001,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-10825176,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-10837472,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-10841972,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-11327849,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-11410275,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-12167037,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-12570729,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-12684014,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-12834367,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-1400382,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-14621983,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-14744126,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-14757767,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-15279575,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-1544485,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-15981999,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-15987690,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-16055923,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-1624956,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-16359643,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-1974463,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-352394,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-352395,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-6098299,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-6098300,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-6109326,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-6268140,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-6994800,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-7018564,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-7018570,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-8388201,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-8808741,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-8823177,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-8987980,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-9507060,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-9735103,
http://linkedlifedata.com/resource/pubmed/commentcorrection/17017804-9757107
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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pubmed:status |
MEDLINE
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pubmed:month |
Oct
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pubmed:issn |
0002-7863
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pubmed:author |
pubmed-author:AndersonVernon EVE,
pubmed-author:BethelChristopher RCR,
pubmed-author:BonomoRobert ARA,
pubmed-author:BuynakJohn DJD,
pubmed-author:CareyMarianne PMP,
pubmed-author:CareyPaul RPR,
pubmed-author:HelfandMarion SMS,
pubmed-author:PadayattiPius SPS,
pubmed-author:SheriAnjaneyuluA,
pubmed-author:TotirMonica AMA,
pubmed-author:van den AkkerFoccoF
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pubmed:issnType |
Print
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pubmed:day |
11
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pubmed:volume |
128
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
13235-42
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pubmed:dateRevised |
2011-9-26
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pubmed:meshHeading |
pubmed-meshheading:17017804-Amines,
pubmed-meshheading:17017804-Binding Sites,
pubmed-meshheading:17017804-Crystallography, X-Ray,
pubmed-meshheading:17017804-Drug Design,
pubmed-meshheading:17017804-Drug Stability,
pubmed-meshheading:17017804-Enzyme Inhibitors,
pubmed-meshheading:17017804-Kinetics,
pubmed-meshheading:17017804-Models, Molecular,
pubmed-meshheading:17017804-Penicillanic Acid,
pubmed-meshheading:17017804-Protein Conformation,
pubmed-meshheading:17017804-Sulfones,
pubmed-meshheading:17017804-beta-Lactamases
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pubmed:year |
2006
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pubmed:articleTitle |
Rational design of a beta-lactamase inhibitor achieved via stabilization of the trans-enamine intermediate: 1.28 A crystal structure of wt SHV-1 complex with a penam sulfone.
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