5dc2 | pdb_00005dc2

X-RAY CRYSTAL STRUCTURE OF A ENZYMATICALLY DEGRADED BIAPENEM-ADDUCT OF L,D-TRANSPEPTIDASE 2 FROM MYCOBACTERIUM TUBERCULOSIS

spinqualitylabelsall models 5dc2, resolution 2.18Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5dc2 is a 2 chain structure with sequence from Mycobacterium tuberculosis CDC1551. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.182Å Ligands: 58U, EDO, GOL, PEG, PGE, SO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function LDT2_MYCTU Generates 3->3 cross-links in peptidoglycan, catalyzing the cleavage of the mDap(3)-D-Ala(4) bond of a tetrapeptide donor stem and the formation of a bond between the carbonyl of mDap(3) of the donor stem and the side chain of mDap(3) of the acceptor stem. Is specific for donor substrates containing a stem tetrapeptide since it cannot use pentapeptide stems. Publication Abstract from PubMed BACKGROUND: The carbapenem subclass of beta-lactams is among the most potent antibiotics available today. Emerging evidence shows that, unlike other subclasses of beta-lactams, carbapenems bind to and inhibit non-classical transpeptidases (L,D-transpeptidases) that generate 3 --> 3 linkages in bacterial peptidoglycan. The carbapenems biapenem and tebipenem exhibit therapeutically valuable potencies against Mycobacterium tuberculosis (Mtb). RESULTS: Here, we report the X-ray crystal structures of Mtb L,D-transpeptidase-2 (LdtMt2) complexed with biapenem or tebipenem. Despite significant variations in carbapenem sulfur side chains, biapenem and tebipenem ultimately form an identical adduct that docks to the outer cavity of LdtMt2. We propose that this common adduct is an enzyme catalyzed decomposition of the carbapenem adduct by a mechanism similar to S-conjugate elimination by beta-lyases. CONCLUSION: The results presented here demonstrate biapenem and tebipenem bind to the outer cavity of LdtMt2, covalently inactivate the enzyme, and subsequently degrade via an S-conjugate elimination mechanism. We discuss structure based drug design based on the findings and propose that the S-conjugate elimination can be leveraged to design novel agents to deliver and locally release antimicrobial factors to act synergistically with the carbapenem carrier. Structural insight into the inactivation of Mycobacterium tuberculosis non-classical transpeptidase LdtMt2 by biapenem and tebipenem.,Bianchet MA, Pan YH, Basta LAB, Saavedra H, Lloyd EP, Kumar P, Mattoo R, Townsend CA, Lamichhane G BMC Biochem. 2017 May 25;18(1):8. doi: 10.1186/s12858-017-0082-4. PMID:28545389 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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