2h5s
From Proteopedia
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| - | [[Image:2h5s.gif|left|200px]] | + | [[Image:2h5s.gif|left|200px]] |
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| - | '''SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase''' | + | {{Structure |
| + | |PDB= 2h5s |SIZE=350|CAPTION= <scene name='initialview01'>2h5s</scene>, resolution 1.28Å | ||
| + | |SITE= | ||
| + | |LIGAND= <scene name='pdbligand=SA2:(3R)-4-[(4-CARBOXYBUTANOYL)OXY]-N-[(1E)-3-OXOPROP-1-EN-1-YL]-3-SULFINO-D-VALINE'>SA2</scene> and <scene name='pdbligand=MA4:CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE'>MA4</scene> | ||
| + | |ACTIVITY= [http://en.wikipedia.org/wiki/Hydrolase Hydrolase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6. 3.5.2.6.] | ||
| + | |GENE= | ||
| + | }} | ||
| + | |||
| + | '''SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase''' | ||
| + | |||
==Overview== | ==Overview== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2H5S is a [ | + | 2H5S is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H5S OCA]. |
==Reference== | ==Reference== | ||
| - | 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., Padayatti PS, Sheri A, Totir MA, Helfand MS, Carey MP, Anderson VE, Carey PR, Bethel CR, Bonomo RA, Buynak JD, van den Akker F, J Am Chem Soc. 2006 Oct 11;128(40):13235-42. PMID:[http:// | + | 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., Padayatti PS, Sheri A, Totir MA, Helfand MS, Carey MP, Anderson VE, Carey PR, Bethel CR, Bonomo RA, Buynak JD, van den Akker F, J Am Chem Soc. 2006 Oct 11;128(40):13235-42. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17017804 17017804] |
[[Category: Hydrolase]] | [[Category: Hydrolase]] | ||
[[Category: Klebsiella pneumoniae]] | [[Category: Klebsiella pneumoniae]] | ||
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[[Category: drug design]] | [[Category: drug design]] | ||
| - | ''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 17:12:58 2008'' |
Revision as of 15:13, 20 March 2008
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| , resolution 1.28Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | and | ||||||
| Activity: | Hydrolase, with EC number 3.5.2.6. | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase
Overview
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.
About this Structure
2H5S is a Single protein structure of sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA.
Reference
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., Padayatti PS, Sheri A, Totir MA, Helfand MS, Carey MP, Anderson VE, Carey PR, Bethel CR, Bonomo RA, Buynak JD, van den Akker F, J Am Chem Soc. 2006 Oct 11;128(40):13235-42. PMID:17017804
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