PDBsum entry 5ueh

Transferase/oxidoreductase

PDB id: 5ueh

Contents

Protein chain

239 a.a.

Ligands

85P

SO4 ×5

GOL

Waters ×216

PDB id:

5ueh

Name:

Transferase/oxidoreductase

Title:

Structure of gsto1 covalently conjugated to quinolinic acid fluorosulfate

Structure:

Glutathione s-transferase omega-1. Chain: a. Synonym: gsto-1,glutathione s-transferase omega 1-1,gsto 1-1, glutathione-dependent dehydroascorbate reductase,monomethylarsonic acid reductase,mma(v) reductase,s-(phenacyl)glutathione reductase, spg-r. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: gsto1, gsttlp28. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.00Å R-factor: 0.173 R-free: 0.230

Authors:

D.E.Mortenson,I.A.Wilson,J.W.Kelly

Key ref:

D.E.Mortenson et al. (2018). "Inverse Drug Discovery" Strategy To Identify Proteins That Are Targeted by Latent Electrophiles As Exemplified by Aryl Fluorosulfates. J Am Chem Soc, 140, 200-210. PubMed id: 29265822

Date:

02-Jan-17 Release date: 17-Jan-18

Protein chain

P78417  (GSTO1_HUMAN) -  Glutathione S-transferase omega-1 from Homo sapiens

Seq: 241 a.a.

Struc: 239 a.a.

Enzyme reactions

• Enzyme class 2: E.C.1.20.4.2 - methylarsonate reductase.
• Reaction: methylarsonate + 2 glutathione + H⁺ = methylarsonous acid + glutathione disulfide + H2O
• Enzyme class 3: E.C.1.8.5.1 - glutathione dehydrogenase (ascorbate).
• Reaction: L-dehydroascorbate + 2 glutathione = glutathione disulfide + L-ascorbate

L-dehydroascorbate + 2 × glutathione (Bound ligand (Het Group name = GOL) matches with 50.00% similarity) = glutathione disulfide + L-ascorbate

• Enzyme class 4: E.C.2.5.1.18 - glutathione transferase.
• Reaction: RX + glutathione = an S-substituted glutathione + a halide anion + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

J Am Chem Soc 140:200-210 (2018)

PubMed id: 29265822

"Inverse Drug Discovery" Strategy To Identify Proteins That Are Targeted by Latent Electrophiles As Exemplified by Aryl Fluorosulfates.

D.E.Mortenson, G.J.Brighty, L.Plate, G.Bare, W.Chen, S.Li, H.Wang, B.F.Cravatt, S.Forli, E.T.Powers, K.B.Sharpless, I.A.Wilson, J.W.Kelly.

ABSTRACT

Drug candidates are generally discovered using biochemical screens employing an isolated target protein or by utilizing cell-based phenotypic assays. Both noncovalent and covalent hits emerge from such endeavors. Herein, we exemplify an "Inverse Drug Discovery" strategy in which organic compounds of intermediate complexity harboring weak, but activatable, electrophiles are matched with the protein(s) they react with in cells or cell lysate. An alkyne substructure in each candidate small molecule enables affinity chromatography-mass spectrometry, which produces a list of proteins that each distinct compound reacts with. A notable feature of this approach is that it is agnostic with respect to the cellular proteins targeted. To illustrate this strategy, we employed aryl fluorosulfates, an underexplored class of sulfur(VI) halides, that are generally unreactive unless activated by protein binding. Reversible aryl fluorosulfate binding, correct juxtaposition of protein side chain functional groups, and transition-state stabilization of the S(VI) exchange reaction all seem to be critical for conjugate formation. The aryl fluorosulfates studied thus far exhibit chemoselective reactivity toward Lys and, particularly, Tyr side chains, and can be used to target nonenzymes (e.g., a hormone carrier or a small-molecule carrier protein) as well as enzymes. The "Inverse Drug Discovery" strategy should be particularly attractive as a means to explore latent electrophiles not typically used in medicinal chemistry efforts, until one reacts with a protein target of exceptional interest. Structure-activity data can then be used to enhance the selectivity of conjugate formation or the covalent probe can be used as a competitor to develop noncovalent drug candidates. Here we use the "Inverse Drug Discovery" platform to identify and validate covalent ligands for 11 different human proteins. In the case of one of these proteins, we have identified and validated a small-molecule probe for the first time.