4k0x

From Proteopedia

(Difference between revisions)

Current revision

X-ray Crystal Structure of OXA-23 from Acinetobacter baumannii

Structural highlights

4k0x is a 1 chain structure with sequence from Acinetobacter baumannii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.61Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

BLO23_ACIBA Class D beta-lactamase which confers resistance to the beta-lactam antibiotics, including ampicillin, and carbapenems such as imipenem and meropenem (PubMed:18725452, PubMed:20194701, PubMed:24012371, PubMed:30530607, PubMed:35420470). Acts via hydrolysis of the beta-lactam ring (PubMed:23877677, PubMed:24012371, PubMed:30530607, PubMed:35420470). Has penicillin-, cephalosporin- and carbapenem-hydrolyzing activities, but lacks ceftazidime-hydrolyzing activity (PubMed:23877677, PubMed:24012371, PubMed:30530607, PubMed:35420470).^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Publication Abstract from PubMed

Class D beta-lactamases that hydrolyze carbapenems such as imipenem and doripenem are a recognized danger to the efficacy of these "last resort" beta-lactam antibiotics. Like all known class D carbapenemases, OXA-23 cannot hydrolyze the expanded-spectrum cephalosporin, ceftazidime. OXA-146 is an OXA-23 subfamily clinical variant that differs from the parent enzyme by a single alanine (A220) inserted in the loop connecting beta-strands beta5 and beta6. We discovered that this insertion enables OXA-146 to bind and hydrolyze ceftazidime with efficiency comparable to other extended-spectrum class D beta-lactamases. OXA-146 also binds and hydrolyzes aztreonam, cefotaxime, ceftriaxone and ampicillin with higher efficiency than OXA-23, and preserves activity against doripenem. In this study, we report the X-ray crystal structures of both the OXA-23 and OXA-146 enzymes at 1.6 A and 1.2 A resolution. A comparison of the two structures shows that the extra alanine moves a methionine (M221) out of its normal position where it forms a bridge over the top of the active site. This single amino acid insertion also lengthens the beta5-beta6 loop, moving the entire backbone of this region further away from the active site. A model of ceftazidime bound in the active site reveals that these two structural alterations are both likely to relieve steric clashes between the bulky R1 side-chain of ceftazidime and OXA-23. With activity against all four classes of beta-lactam antibiotics, OXA-146 represents an alarming new threat to the treatment of infections caused by Acinetobacter spp.

STRUCTURES OF THE CLASS D CARBAPENEMASES OXA-23 AND OXA-146: MECHANISTIC BASIS OF ACTIVITY AGAINST CARBAPENEMS, EXTENDED-SPECTRUM CEPHALOSPORINS AND AZTREONAM.,Kaitany KC, Klinger NV, June CM, Ramey ME, Bonomo RA, Powers RA, Leonard DA Antimicrob Agents Chemother. 2013 Jul 22. PMID:23877677^[7]

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

References

↑ Adams-Haduch JM, Paterson DL, Sidjabat HE, Pasculle AW, Potoski BA, Muto CA, Harrison LH, Doi Y. Genetic basis of multidrug resistance in Acinetobacter baumannii clinical isolates at a tertiary medical center in Pennsylvania. Antimicrob Agents Chemother. 2008 Nov;52(11):3837-43. PMID:18725452 doi:10.1128/AAC.00570-08
↑ Lin YC, Hsia KC, Chen YC, Sheng WH, Chang SC, Liao MH, Li SY. Genetic basis of multidrug resistance in Acinetobacter clinical isolates in Taiwan. Antimicrob Agents Chemother. 2010 May;54(5):2078-84. PMID:20194701 doi:10.1128/AAC.01398-09
↑ Kaitany KC, Klinger NV, June CM, Ramey ME, Bonomo RA, Powers RA, Leonard DA. STRUCTURES OF THE CLASS D CARBAPENEMASES OXA-23 AND OXA-146: MECHANISTIC BASIS OF ACTIVITY AGAINST CARBAPENEMS, EXTENDED-SPECTRUM CEPHALOSPORINS AND AZTREONAM. Antimicrob Agents Chemother. 2013 Jul 22. PMID:23877677 doi:10.1128/AAC.00762-13
↑ Smith CA, Antunes NT, Stewart NK, Toth M, Kumarasiri M, Chang M, Mobashery S, Vakulenko SB. Structural Basis for Carbapenemase Activity of the OXA-23 beta-Lactamase from Acinetobacter baumannii. Chem Biol. 2013 Sep 19;20(9):1107-15. doi: 10.1016/j.chembiol.2013.07.015. Epub, 2013 Sep 5. PMID:24012371 doi:10.1016/j.chembiol.2013.07.015
↑ Stewart NK, Smith CA, Antunes NT, Toth M, Vakulenko SB. Role of the Hydrophobic Bridge in the Carbapenemase Activity of Class D beta-Lactamases. Antimicrob Agents Chemother. 2018 Dec 10. pii: AAC.02191-18. doi:, 10.1128/AAC.02191-18. PMID:30530607 doi:http://dx.doi.org/10.1128/AAC.02191-18
↑ Stewart NK, Toth M, Alqurafi MA, Chai W, Nguyen TQ, Quan P, Lee M, Buynak JD, Smith CA, Vakulenko SB. C6 Hydroxymethyl-Substituted Carbapenem MA-1-206 Inhibits the Major Acinetobacter baumannii Carbapenemase OXA-23 by Impeding Deacylation. mBio. 2022 Apr 14:e0036722. doi: 10.1128/mbio.00367-22. PMID:35420470 doi:http://dx.doi.org/10.1128/mbio.00367-22
↑ Kaitany KC, Klinger NV, June CM, Ramey ME, Bonomo RA, Powers RA, Leonard DA. STRUCTURES OF THE CLASS D CARBAPENEMASES OXA-23 AND OXA-146: MECHANISTIC BASIS OF ACTIVITY AGAINST CARBAPENEMS, EXTENDED-SPECTRUM CEPHALOSPORINS AND AZTREONAM. Antimicrob Agents Chemother. 2013 Jul 22. PMID:23877677 doi:10.1128/AAC.00762-13

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/4k0x"

@@ Line 1: / Line 1: @@
 ==X-ray Crystal Structure of OXA-23 from Acinetobacter baumannii==
-<StructureSection load='4k0x' size='340' side='right' caption='[[4k0x]], [[Resolution|resolution]] 1.61&Aring;' scene=''>
+<StructureSection load='4k0x' size='340' side='right'caption='[[4k0x]], [[Resolution|resolution]] 1.61&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4k0x]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Aciba Aciba]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K0X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4K0X FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4k0x]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Acinetobacter_baumannii Acinetobacter baumannii]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4K0X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4K0X FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.61&#8491;</td></tr>
-<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BCT:BICARBONATE+ION'>BCT</scene>, <scene name='pdbligand=KCX:LYSINE+NZ-CARBOXYLIC+ACID'>KCX</scene></td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4k0w|4k0w]]</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4k0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k0x OCA], [https://pdbe.org/4k0x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4k0x RCSB], [https://www.ebi.ac.uk/pdbsum/4k0x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4k0x ProSAT]</span></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">ari-1, bla(OXA-23), bla-OXA-23, blaOXA-23, OXA-23, oxa23 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=470 ACIBA])</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4k0x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4k0x OCA], [http://pdbe.org/4k0x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4k0x RCSB], [http://www.ebi.ac.uk/pdbsum/4k0x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4k0x ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/BLO23_ACIBA BLO23_ACIBA] Class D beta-lactamase which confers resistance to the beta-lactam antibiotics, including ampicillin, and carbapenems such as imipenem and meropenem (PubMed:18725452, PubMed:20194701, PubMed:24012371, PubMed:30530607, PubMed:35420470). Acts via hydrolysis of the beta-lactam ring (PubMed:23877677, PubMed:24012371, PubMed:30530607, PubMed:35420470). Has penicillin-, cephalosporin- and carbapenem-hydrolyzing activities, but lacks ceftazidime-hydrolyzing activity (PubMed:23877677, PubMed:24012371, PubMed:30530607, PubMed:35420470).<ref>PMID:18725452</ref> <ref>PMID:20194701</ref> <ref>PMID:23877677</ref> <ref>PMID:24012371</ref> <ref>PMID:30530607</ref> <ref>PMID:35420470</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 21: @@
 ==See Also==
-*[[Beta-lactamase|Beta-lactamase]]
+*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Aciba]]
+[[Category: Acinetobacter baumannii]]
-[[Category: Beta-lactamase]]
+[[Category: Large Structures]]
-[[Category: Klinger, N V]]
+[[Category: Klinger NV]]
-[[Category: Leonard, D A]]
+[[Category: Leonard DA]]
-[[Category: Powers, R A]]
+[[Category: Powers RA]]
-[[Category: Ramey, M E]]
+[[Category: Ramey ME]]
-[[Category: Carbapenemase]]
-[[Category: Hydrolase]]

4k0x

From Proteopedia

Current revision

X-ray Crystal Structure of OXA-23 from Acinetobacter baumannii

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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