2h5s
From Proteopedia
(New page: 200px<br /><applet load="2h5s" size="450" color="white" frame="true" align="right" spinBox="true" caption="2h5s, resolution 1.28Å" /> '''SA2-13 penam sulfone...) |
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| - | [[Image:2h5s.gif|left|200px]]<br /><applet load="2h5s" size=" | + | [[Image:2h5s.gif|left|200px]]<br /><applet load="2h5s" size="350" color="white" frame="true" align="right" spinBox="true" |
caption="2h5s, resolution 1.28Å" /> | caption="2h5s, resolution 1.28Å" /> | ||
'''SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase'''<br /> | '''SA2-13 penam sulfone complexed to wt SHV-1 beta-lactamase'''<br /> | ||
==Overview== | ==Overview== | ||
| - | beta-Lactamases are one of the major causes of antibiotic resistance in | + | 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== | ==About this Structure== | ||
| - | 2H5S is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae] with SA2 and MA4 as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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.] Full crystallographic information is available from [http:// | + | 2H5S is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae] with <scene name='pdbligand=SA2:'>SA2</scene> and <scene name='pdbligand=MA4:'>MA4</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [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.] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2H5S OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Klebsiella pneumoniae]] | [[Category: Klebsiella pneumoniae]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Akker, F | + | [[Category: Akker, F van den.]] |
| - | [[Category: Padayatti, P | + | [[Category: Padayatti, P S.]] |
[[Category: MA4]] | [[Category: MA4]] | ||
[[Category: SA2]] | [[Category: SA2]] | ||
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[[Category: drug design]] | [[Category: drug design]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:38:27 2008'' |
Revision as of 15:38, 21 February 2008
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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 with and as ligands. Active as Hydrolase, with EC number 3.5.2.6. 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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