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000902474 1001_ $$0P:(DE-Juel1)190226$$aAhmad, Sabahuddin$$b0
000902474 245__ $$aSubstrate Access Mechanism in a Novel Membrane-Bound Phospholipase A of Pseudomonas aeruginosa Concordant with Specificity and Regioselectivity
000902474 260__ $$aWashington, DC$$bAmerican Chemical Society$$c2021
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000902474 520__ $$aPlaF is a cytoplasmic membrane-bound phospholipase A1 from Pseudomonas aeruginosa that alters the membrane glycerophospholipid (GPL) composition and fosters the virulence of this human pathogen. PlaF activity is regulated by a dimer-to-monomer transition followed by tilting of the monomer in the membrane. However, how substrates reach the active site and how the characteristics of the active site tunnels determine the activity, specificity, and regioselectivity of PlaF for natural GPL substrates have remained elusive. Here, we combined unbiased and biased all-atom molecular dynamics (MD) simulations and configurational free-energy computations to identify access pathways of GPL substrates to the catalytic center of PlaF. Our results map out a distinct tunnel through which substrates access the catalytic center. PlaF variants with bulky tryptophan residues in this tunnel revealed decreased catalysis rates due to tunnel blockage. The MD simulations suggest that GPLs preferably enter the active site with the sn-1 acyl chain first, which agrees with the experimentally demonstrated PLA1 activity of PlaF. We propose that the acyl chain-length specificity of PlaF is determined by the structural features of the access tunnel, which results in favorable free energy of binding of medium-chain GPLs. The suggested egress route conveys fatty acid (FA) products to the dimerization interface and, thus, contributes to understanding the product feedback regulation of PlaF by FA-triggered dimerization. These findings open up opportunities for developing potential PlaF inhibitors, which may act as antibiotics against P. aeruginosa.
000902474 536__ $$0G:(DE-HGF)POF4-2171$$a2171 - Biological and environmental resources for sustainable use (POF4-217)$$cPOF4-217$$fPOF IV$$x0
000902474 536__ $$0G:(DE-HGF)POF4-5111$$a5111 - Domain-Specific Simulation & Data Life Cycle Labs (SDLs) and Research Groups (POF4-511)$$cPOF4-511$$fPOF IV$$x1
000902474 536__ $$0G:(DE-Juel1)hkf7_20200501$$aForschergruppe Gohlke (hkf7_20200501)$$chkf7_20200501$$fForschergruppe Gohlke$$x2
000902474 536__ $$0G:(GEPRIS)267205415$$aDFG project 267205415 - SFB 1208: Identität und Dynamik von Membransystemen - von Molekülen bis zu zellulären Funktionen (267205415)$$c267205415$$x3
000902474 588__ $$aDataset connected to CrossRef, Journals: juser.fz-juelich.de
000902474 7001_ $$0P:(DE-Juel1)169449$$aStrunk, Christoph Heinrich$$b1
000902474 7001_ $$0P:(DE-Juel1)187014$$aSchott, Stephan$$b2$$ufzj
000902474 7001_ $$0P:(DE-Juel1)131457$$aJaeger, Karl-Erich$$b3
000902474 7001_ $$0P:(DE-Juel1)131480$$aKovacic, Filip$$b4$$eCorresponding author
000902474 7001_ $$0P:(DE-Juel1)172663$$aGohlke, Holger$$b5$$eCorresponding author
000902474 773__ $$0PERI:(DE-600)1491237-5$$a10.1021/acs.jcim.1c00973$$gp. acs.jcim.1c00973$$n11$$p5626–5643$$tJournal of chemical information and modeling$$v61$$x0095-2338$$y2021
000902474 8564_ $$uhttps://juser.fz-juelich.de/record/902474/files/PlaF_activity_rev_final.pdf$$yPublished on 2021-11-08. Available in OpenAccess from 2022-11-08.
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000902474 9141_ $$y2021
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