4s2p

Crystal structure of unbound OXA-48

Structural highlights

4s2p is a 2 chain structure with sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.7Å
Ligands:	KCX
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BLO48_KLEPN Class D beta-lactamase which confers resistance to the beta-lactam antibiotics, including amoxicillin, and moderate resistance to cephalosporins and carbapenems such as cephalothin and imipenem; in the DH10B strain of E.coli (PubMed:14693513). Acts via hydrolysis of the beta-lactam ring (PubMed:14693513, PubMed:19477418, PubMed:27073009, PubMed:38161376). Has oxacillin-, cephalothin- and imipenem-hydrolyzing activities (PubMed:14693513, PubMed:19477418, PubMed:27073009, PubMed:38161376).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Emerging beta-lactamase-mediated resistance is threatening the clinical utility of the single most prominent class of antibacterial agents used in medicine, the beta-lactams. The diazabicyclooctane avibactam is able to inhibit a wider range of serine beta-lactamases than has been previously observed with beta-lactamase inhibitors such as the widely prescribed clavulanic acid. However, despite its broad-spectrum activity, variable levels of inhibition have been observed for molecular class D beta-lactamases. In order to better understand the molecular basis and spectrum of inhibition by avibactam, we provide structural and mechanistic analysis of the compound in complex with important class A and D serine beta-lactamases. Herein, we reveal the 1.7- and 2.0-A-resolution crystal structures of avibactam covalently bound to class D beta-lactamases OXA-10 and OXA-48. Furthermore, a kinetic analysis of key active-site mutants for class A beta-lactamase CTX-M-15 allows us to propose a validated mechanism for avibactam-mediated beta-lactamase inhibition including a unique role for S130, which acts as a general base. This study provides molecular insights that will aid in the design and development of avibactam-based chemotherapeutic agents effective against emerging drug-resistant microorganisms.

Molecular Mechanism of Avibactam-Mediated beta-Lactamase Inhibition.,King DT, King AM, Lal SM, Wright GD, Strynadka NC ACS Infect Dis. 2015 Apr 10;1(4):175-84. doi: 10.1021/acsinfecdis.5b00007. Epub, 2015 Feb 11. PMID:27622530^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Poirel L, Héritier C, Tolün V, Nordmann P. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2004 Jan;48(1):15-22. PMID:14693513 doi:10.1128/AAC.48.1.15-22.2004
↑ Docquier JD, Calderone V, De Luca F, Benvenuti M, Giuliani F, Bellucci L, Tafi A, Nordmann P, Botta M, Rossolini GM, Mangani S. Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemases. Chem Biol. 2009 May 29;16(5):540-7. PMID:19477418 doi:10.1016/j.chembiol.2009.04.010
↑ Stojanoski V, Adamski CJ, Hu L, Mehta SC, Sankaran B, Zwart P, Prasad BV, Palzkill T. Removal of the Side Chain at the Active-Site Serine by a Glycine Substitution Increases the Stability of a Wide Range of Serine beta-Lactamases by Relieving Steric Strain. Biochemistry. 2016 May 3;55(17):2479-90. doi: 10.1021/acs.biochem.6b00056. Epub, 2016 Apr 22. PMID:27073009 doi:https://dx.doi.org/10.1021/acs.biochem.6b00056
↑ Zhou Q, Catalán P, Bell H, Baumann P, Cooke R, Evans R, Yang J, Zhang Z, Zappalà D, Zhang Y, Blackburn GM, He Y, Jin Y. An Ion-Pair Induced Intermediate Complex Captured in Class D Carbapenemase Reveals Chloride Ion as a Janus Effector Modulating Activity. ACS Cent Sci. 2023 Dec 13;9(12):2339-2349. PMID:38161376 doi:10.1021/acscentsci.3c00609
↑ King DT, King AM, Lal SM, Wright GD, Strynadka NC. Molecular Mechanism of Avibactam-Mediated beta-Lactamase Inhibition. ACS Infect Dis. 2015 Apr 10;1(4):175-84. doi: 10.1021/acsinfecdis.5b00007. Epub, 2015 Feb 11. PMID:27622530 doi:https://dx.doi.org/10.1021/acsinfecdis.5b00007

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OCA

[1] Poirel L, Héritier C, Tolün V, Nordmann P. Emergence of oxacillinase-mediated resistance to imipenem in Klebsiella pneumoniae. Antimicrob Agents Chemother. 2004 Jan;48(1):15-22. PMID:14693513 doi:10.1128/AAC.48.1.15-22.2004

[2] Docquier JD, Calderone V, De Luca F, Benvenuti M, Giuliani F, Bellucci L, Tafi A, Nordmann P, Botta M, Rossolini GM, Mangani S. Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemases. Chem Biol. 2009 May 29;16(5):540-7. PMID:19477418 doi:10.1016/j.chembiol.2009.04.010

[3] Stojanoski V, Adamski CJ, Hu L, Mehta SC, Sankaran B, Zwart P, Prasad BV, Palzkill T. Removal of the Side Chain at the Active-Site Serine by a Glycine Substitution Increases the Stability of a Wide Range of Serine beta-Lactamases by Relieving Steric Strain. Biochemistry. 2016 May 3;55(17):2479-90. doi: 10.1021/acs.biochem.6b00056. Epub, 2016 Apr 22. PMID:27073009 doi:https://dx.doi.org/10.1021/acs.biochem.6b00056

[4] Zhou Q, Catalán P, Bell H, Baumann P, Cooke R, Evans R, Yang J, Zhang Z, Zappalà D, Zhang Y, Blackburn GM, He Y, Jin Y. An Ion-Pair Induced Intermediate Complex Captured in Class D Carbapenemase Reveals Chloride Ion as a Janus Effector Modulating Activity. ACS Cent Sci. 2023 Dec 13;9(12):2339-2349. PMID:38161376 doi:10.1021/acscentsci.3c00609

[5] King DT, King AM, Lal SM, Wright GD, Strynadka NC. Molecular Mechanism of Avibactam-Mediated beta-Lactamase Inhibition. ACS Infect Dis. 2015 Apr 10;1(4):175-84. doi: 10.1021/acsinfecdis.5b00007. Epub, 2015 Feb 11. PMID:27622530 doi:https://dx.doi.org/10.1021/acsinfecdis.5b00007

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4s2p

Crystal structure of unbound OXA-48

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

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