This old version of Proteopedia is provided for student assignments while the new version is undergoing repairs. Content and edits done in this old version of Proteopedia after March 1, 2026 will eventually be lost when it is retired in about June of 2026.
Apply for new accounts at the new Proteopedia. Your logins will work in both the old and new versions.
2h5s
From Proteopedia
| Line 1: | Line 1: | ||
| - | [[Image:2h5s.gif|left|200px]] | + | [[Image:2h5s.gif|left|200px]] |
| - | + | ||
| - | '''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== | ||
| Line 7: | Line 16: | ||
==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]] | ||
| Line 21: | Line 30: | ||
[[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
| |||||||
| , 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
Page seeded by OCA on Thu Mar 20 17:12:58 2008
