5I0U

Incompletely interpreted D-cysteine soak of Cysteine Dioxygenase at pH 7.0

Summary for 5I0U

• Entry DOI: 10.2210/pdb5i0u/pdb
• Related: 5I0R 5I0S 5I0T
• Descriptor: Cysteine dioxygenase type 1, FE (III) ION, D-CYSTEINE, ... (4 entities in total)
• Functional Keywords: cupin-fold, cysteine to cysteine sulfinate, c93-y157 crosslink, d-cysteine, catalysis oxidation, oxidoreductase
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 1
• Total formula weight: 23267.96

Authors

Kean, K.M.,Driggers, C.M.,Karplus, P.A. (deposition date: 2016-02-04, release date: 2017-02-22, Last modification date: 2024-10-16)

Primary citation

Driggers, C.M.,Kean, K.M.,Hirschberger, L.L.,Cooley, R.B.,Stipanuk, M.H.,Karplus, P.A.
Structure-Based Insights into the Role of the Cys-Tyr Crosslink and Inhibitor Recognition by Mammalian Cysteine Dioxygenase.
J. Mol. Biol., 428:3999-4012, 2016

PubMed Abstract: In mammals, the non-heme iron enzyme cysteine dioxygenase (CDO) helps regulate Cys levels through converting Cys to Cys sulfinic acid. Its activity is in part modulated by the formation of a Cys93-Tyr157 crosslink that increases its catalytic efficiency over 10-fold. Here, 21 high-resolution mammalian CDO structures are used to gain insight into how the Cys-Tyr crosslink promotes activity and how select competitive inhibitors bind. Crystal structures of crosslink-deficient C93A and Y157F variants reveal similar ~1.0-Å shifts in the side chain of residue 157, and both variant structures have a new chloride ion coordinating the active site iron. Cys binding is also different from wild-type CDO, and no Cys-persulfenate forms in the C93A or Y157F active sites at pH6.2 or 8.0. We conclude that the crosslink enhances activity by positioning the Tyr157 hydroxyl to enable proper Cys binding, proper oxygen binding, and optimal chemistry. In addition, structures are presented for homocysteine (Hcy), D-Cys, thiosulfate, and azide bound as competitive inhibitors. The observed binding modes of Hcy and D-Cys clarify why they are not substrates, and the binding of azide shows that in contrast to what has been proposed, it does not bind in these crystals as a superoxide mimic.

PubMed: 27477048
DOI: 10.1016/j.jmb.2016.07.012

Experimental method

X-RAY DIFFRACTION (1.25 Å)