2013
DOI: 10.1371/journal.pcbi.1003155
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Variations within Class-A β-Lactamase Physiochemical Properties Reflect Evolutionary and Environmental Patterns, but not Antibiotic Specificity

Abstract: The bacterial enzyme β-lactamase hydrolyzes the β-lactam ring of penicillin and chemically related antibiotics, rendering them ineffective. Due to rampant antibiotic overuse, the enzyme is evolving new resistance activities at an alarming rate. Related, the enzyme's global physiochemical properties exhibit various amounts of conservation and variability across the family. To that end, we characterize the extent of property conservation within twelve different class-A β-lactamases, and conclusively establish th… Show more

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Cited by 21 publications
(16 citation statements)
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“…Taken together, the above results demonstrate that T m is robust at N rep ≥6, whereas the mechanical properties are robust at much smaller values of N rep , which is consistent with our earlier results [25]. Upon careful inspection, low similarity pairs are more frequent in CC, relative to FI, which is also consistent with our prior results [25], [33], [34], [35], [57], [58], [59]. Good convergence to consistent results is obtained when representative structures are selected from each cluster at random (data not shown).…”
Section: Resultssupporting
confidence: 91%
“…Taken together, the above results demonstrate that T m is robust at N rep ≥6, whereas the mechanical properties are robust at much smaller values of N rep , which is consistent with our earlier results [25]. Upon careful inspection, low similarity pairs are more frequent in CC, relative to FI, which is also consistent with our prior results [25], [33], [34], [35], [57], [58], [59]. Good convergence to consistent results is obtained when representative structures are selected from each cluster at random (data not shown).…”
Section: Resultssupporting
confidence: 91%
“…There are four different BL classes, and the class-A enzymes are the most clinically relevant. Interestingly, the TEM-1 class-A enzyme has been shown to have an extremely rigid backbone (16), which is consistent with our results (17). Moreover, our backbone flexibility predictions are well conserved across the family, whereas allosteric couplings are overall quite variable.…”
Section: Introductionsupporting
confidence: 92%
“…As discussed above, the MPM correctly identifies the phosphorylation site as allosteric in three chemotaxis protein Y orthologs (26), which is the only conserved site identified across the set. As with the MPM results, our collective results reveal CC to be very sensitive to sequence and structural variations across protein families (28,30,31,(44)(45)(46)(47)(48)(49)(50), which is in complete agreement with various experimental comparisons of allosteric effects across protein families. Going as far back as 1970 (51), quantifiable differences in allosteric response have been used as a taxonomic marker in the 3-deoxy-D-arabino-heptulosonate-7-phosphate synthetase family.…”
Section: Relationship To Experimental Characterizationssupporting
confidence: 87%