6KGU

Crystal structure of Penicillin binding protein 3 (PBP3) from Mycobacterium tuerculosis, complexed with aztreonam

Summary for 6KGU

• Entry DOI: 10.2210/pdb6kgu/pdb
• Descriptor: Penicillin-binding protein PbpB, 2-({[(1Z)-1-(2-amino-1,3-thiazol-4-yl)-2-oxo-2-{[(2S,3S)-1-oxo-3-(sulfoamino)butan-2-yl]amino}ethylidene]amino}oxy)-2-methylpropanoic acid, COBALT (II) ION, ... (4 entities in total)
• Functional Keywords: penicillin-binding protein, native form, mycobacterium tuberculosis, aztreonam, transferase
• Biological source: Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
• Total number of polymer chains: 1
• Total formula weight: 60415.26

Authors

Lu, Z.K.,Zhang, A.L.,Liu, X.,Guddat, L.,Yang, H.T.,Rao, Z.H. (deposition date: 2019-07-12, release date: 2020-03-11, Last modification date: 2024-10-30)

Primary citation

Lu, Z.,Wang, H.,Zhang, A.,Liu, X.,Zhou, W.,Yang, C.,Guddat, L.,Yang, H.,Schofield, C.J.,Rao, Z.
Structures ofMycobacterium tuberculosisPenicillin-Binding Protein 3 in Complex with Fivebeta-Lactam Antibiotics Reveal Mechanism of Inactivation.
Mol.Pharmacol., 97:287-294, 2020

PubMed Abstract: Because of -lactamase-mediated resistance, -lactam antibiotics were long considered ineffective drugs for tuberculosis (TB) treatment. However, some -lactams, including meropenem and faropenem, are being re-evaluated in patients infected with TB. Penicillin-binding protein (PBP) 3, or ftsI, is an essential transpeptidase in required for cell division, and thus it is an important drug target. Structures of apo PBP3 and of complexes with five -lactams, including meropenem and faropenem, reveal how they cause inactivation via formation of hydrolytically stable acyl-enzyme complexes. The structures reveal unique features of the antibiotic interactions, both in terms of differences in their binding to PBP3 and in comparison with structures of other PBPs and serine -lactamases, including the tautomerization status of the carbapenem-derived acyl-enzyme complexes. The results suggest that rather than PBP inhibitors developed for other infections will work against TB, work should focus on developing PBP inhibitors for treating TB. SIGNIFICANCE STATEMENT: The structures of penicillin-binding protein 3, an essential protein in , in complex with a number of widely used -lactam antibiotics (e.g., meropenem, aztreonam, and amoxicillin) were solved. These data provide new insights for next-generation rational approaches to design tuberculosis (TB)-specific -lactam or nonlactam antibiotics. This manuscript is a seminal article in the field of anti-TB drug discovery and suitable for the broad readership.

PubMed: 32086254
DOI: 10.1124/mol.119.118042

Experimental method

X-RAY DIFFRACTION (2.106 Å)