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Structures of Cys319 variants and acetohydroxamate-inhibited Klebsiella aerogenes urease.

Pearson MA, Michel LO, Hausinger RP, Karplus PA
Biochemistry 36 8164-72 (1997)
Related entries: 1fwa, 1fwc, 1fwd, 1fwe, 1fwf, 1fwg, 1fwh, 1fwj, 1kra, 1krb, 1krc, 2kau

Cited: 60 times
EuropePMC logo PMID: 9201965

Abstract

Cys319 is located on a mobile flap covering the active site of Klebsiella aerogenes urease but does not play an essential role in catalysis. Four urease variants altered at position C319 range from having high activity (C319A) to no measurable activity (C319Y), indicating Cys is not required at this position, but its presence is highly influential [Martin, P. R., & Hausinger, R. P. (1992) J. Biol. Chem. 267, 20024-20027]. Here, we present 2.0 A resolution crystal structures of C319A, C319S, C319D, and C319Y proteins and the C319A variant inhibited by acetohydroxamic acid. These structures show changes in the hydration of the active site nickel ions and in the position and flexibility of the active site flap. The C319Y protein exhibits an alternate conformation of the flap, explaining its lack of activity. The changes in hydration and conformation suggest that there are suboptimal protein-solvent and protein-protein interactions in the empty urease active site which contribute to urease catalysis. Specifically, we hypothesize that the suboptimal interactions may provide a significant source of substrate binding energy, and such hidden energy may be a common phenomenon for enzymes that contain mobile active site loops and undergo an induced fit. The acetohydroxamic acid-bound structure reveals a chelate interaction similar to those seen in other metalloenzymes and in a small molecule nickel complex. The inhibitor binding mode supports the proposed mode of urea binding. We complement these structural studies with extended functional studies of C319A urease to show that it has enhanced stability and resistance to inhibition by buffers containing nickel ions. The near wild-type activity and enhanced stability of the C319A variant make it useful for further studies of urease structure-function relationships.

Reviews - 1fwb mentioned but not cited (1)

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Reviews citing this publication (13)

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Related citations provided by authors (4)

  1. Structures of the Klebsiella aerogenes urease apoenzyme and two active-site mutants.. Jabri E, Karplus PA Biochemistry 35 10616-26 (1996)
  2. The crystal structure of urease from Klebsiella aerogenes.. Jabri E, Carr MB, Hausinger RP, Karplus PA Science 268 998-1004 (1995)
  3. Site-directed mutagenesis of the active site cysteine in Klebsiella aerogenes urease.. Martin PR, Hausinger RP J Biol Chem 267 20024-7 (1992)
  4. Identification of the essential cysteine residue in Klebsiella aerogenes urease.. Todd MJ, Hausinger RP J Biol Chem 266 24327-31 (1991)

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