Genetic Mutations in the S-loop of Human Glutathione Synthetase: Links Between Substrate Binding, Active Site Structure and Allostery.


Abstract

The second step in the biosynthesis of the cellular antioxidant glutathione (GSH) is catalyzed by human glutathione synthetase (hGS), a negatively cooperative homodimer. Patients with mutations in hGS have been reported to exhibit a range of symptoms from hemolytic anemia and metabolic acidosis to neurological disorders and premature death. Several patient mutations occur in the S-loop of hGS, a series of residues near the negatively cooperative γ-GC substrate binding site. Experimental point mutations and molecular dynamic simulations show the S-loop not only binds γ-GC through a salt bridge and multiple hydrogen bonds, but the residues also modulate allosteric communication in hGS. By elucidating the role of S-loop residues in active site structure, substrate binding, and allostery, the atomic level sequence of events that leads to the detrimental effects of hGS mutations in patients are more fully understood.

Submission Details

ID: QCsa57PB3

Submitter: Shu-Ching Ou

Submission Date: March 7, 2019, 3:22 p.m.

Version: 1

Publication Details
Ingle BL;Shrestha B;De Jesus MC;Conrad-Webb HM;Anderson ME;Cundari TR,Comput Struct Biotechnol J (2019) Genetic Mutations in the S-loop of Human Glutathione Synthetase: Links Between Substrate Binding, Active Site Structure and Allostery. PMID:30581542
Additional Information

ND = activity too low to determine.

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant PDB Entries

Structure ID Release Date Resolution Structure Title
2HGS 1999-06-22 2.1 HUMAN GLUTATHIONE SYNTHETASE

Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Glutathione synthetase P48637 GSHB_HUMAN
97.5 Glutathione synthetase Q8HXX5 GSHB_MACFA
91.1 Glutathione synthetase Q5EAC2 GSHB_BOVIN