The crystallography endstation at beamline P11 at PETRA III

Burkhardt, Anja; Reime, B.; Pakendorf, Tim; Roever, Jan; Stuebe, Nicolas; Meyer, Jan; Fischer, P.; Panneerselvam, S.; Meents, A.

doi:10.1107/s0108767313096505

Cited by 1 publication

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“…All X-ray diffraction data were collected using synchrotron radiation at 100 K (Beamline P11, Petra III, DESY, Hamburg, Germany) 50 . The diffraction data were processed using the XDS program package 51 at resolutions of 1.3 Å for the Bortezomib-complex, 1.1 Å for the Ixazomib-complex and 1.0 Å for the inhibitor-free CTX-M-14 enzyme, all in space group P2 1 2 1 2 1 (Table S1 ).…”

Section: Methodsmentioning

confidence: 99%

Structural basis to repurpose boron-based proteasome inhibitors Bortezomib and Ixazomib as β-lactamase inhibitors

Perbandt

Werner

Rohde

et al. 2022

Sci Rep

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Abstractβ-lactamases are a major cause of rapidly emerging and spreading antibiotic resistance. Currently β-lactamase inhibitors (BLIs) in clinical use act only on Ambler Class A, C and some class D lactamases. The urgent need to identify new BLIs recently lead to FDA approval of boron-based compounds BLIs, e.g. Vaborbactam. The boron-based proteasome inhibitors Bortezomib and Ixazomib are used in cancer therapy as multiple myeloma drugs but they also bind to Ser-/Thr- proteases. In this study we show the crystal structures of the β-lactamase CTX-M-14 with covalently bound Bortezomib and Ixazomib at high resolutions of 1.3 and 1.1 Å, respectively. Ixazomib is well defined in electron density whereas Bortezomib show some disorder which corresponds to weaker inhibition efficiency observed for Ixazomib. Both inhibitors mimic the deacylation transition state of β-lactam hydrolysis, because they replace the deacylating water molecule. We further investigate differences in binding of Bortezomib/Ixazomib to CTX-M-14 and its target proteases as well as known β-lactamase drugs. Our findings can help to use Bortezomib/Ixazomib as lead compounds for development of new BLIs.

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Section: Methodsmentioning

confidence: 99%