Cryptic Binding Pockets in PDC‑3 β‑Lactamase Modulate Resistance Profiles
Shuang Chen, Fedaa Attana, Andrea M. Hujer, Christopher R. Bethel, Magdalena A. Taracila, Robert A. Bonomo, Shozeb Haider
TL;DR
This study reveals hidden protein conformations in PDC-3 β-lactamase that influence antibiotic resistance and could guide new drug design.
Contribution
A novel framework combining enhanced sampling and deep learning to uncover cryptic pockets and conformational states in β-lactamase.
Findings
Three distinct conformational states of the Ω-loop in PDC-3 were identified, including a constricted state blocking the catalytic site.
Residues 219 and 221 act as molecular switches that modulate resistance profiles by shifting between these states.
A previously unseen cryptic pocket was discovered, offering a potential allosteric target for inhibitors.
Abstract
Cryptic binding pockets in proteins can modulate catalysis, allostery, and druggability. Yet they are rarely captured by experiments or conventional molecular dynamics simulations. Here, we combine enhanced sampling with an unsupervised deep-learning pipeline to map the full conformational landscape of the Ω-loop in class C β-lactamase PDC-3. Three principal conformational ensembles were identified: a crystal-like state resembling the native structure, an expansive state characterized by widening of the active-site cleft, and a constricted state that blocks access to the catalytic site. Residues 219 and 221 act as molecular switches that shuffle the enzyme between these states and thereby modulate the resistance profiles. Steady-state inhibition assays with nitrocefin and bulky cephalosporins confirm that substitutions at these positions selectively reshaped the binding pocket. In…
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Taxonomy
TopicsAntibiotic Resistance in Bacteria · Protein Structure and Dynamics · Enzyme Structure and Function