2h5s
From Proteopedia
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|PDB= 2h5s |SIZE=350|CAPTION= <scene name='initialview01'>2h5s</scene>, resolution 1.28Å | |PDB= 2h5s |SIZE=350|CAPTION= <scene name='initialview01'>2h5s</scene>, resolution 1.28Å | ||
|SITE= | |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> | + | |LIGAND= <scene name='pdbligand=MA4:CYCLOHEXYL-HEXYL-BETA-D-MALTOSIDE'>MA4</scene>, <scene name='pdbligand=SA2:(3R)-4-[(4-CARBOXYBUTANOYL)OXY]-N-[(1E)-3-OXOPROP-1-EN-1-YL]-3-SULFINO-D-VALINE'>SA2</scene> |
| - | + | |ACTIVITY= <span class='plainlinks'>[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.] </span> | |
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY=[[1rcj|1RCJ]] | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2h5s FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2h5s OCA], [http://www.ebi.ac.uk/pdbsum/2h5s PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2h5s RCSB]</span> | ||
}} | }} | ||
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[[Category: Akker, F van den.]] | [[Category: Akker, F van den.]] | ||
[[Category: Padayatti, P S.]] | [[Category: Padayatti, P S.]] | ||
| - | [[Category: MA4]] | ||
| - | [[Category: SA2]] | ||
[[Category: beta-lactamase inhibitor]] | [[Category: beta-lactamase inhibitor]] | ||
[[Category: drug design]] | [[Category: drug design]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:25:50 2008'' |
Revision as of 00:25, 31 March 2008
| |||||||
| , resolution 1.28Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Activity: | Hydrolase, with EC number 3.5.2.6. | ||||||
| Related: | 1RCJ
| ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| 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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