PDBsum entry 1ebv

Oxidoreductase

PDB id

1ebv

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Contents

			Protein chain

					551 a.a. *

			Ligands

					NAG-NAG


					NAG ×2


					SCL


					HEM

* Residue conservation analysis

PDB id:

1ebv

Links

Name:

Oxidoreductase

Title:

Ovine pghs-1 complexed with salicyl hydroxamic acid

Structure:

Prostaglandin h2 synthase. Chain: a. Ec: 1.14.99.1

Source:

Ovis aries. Sheep. Organism_taxid: 9940. Organ: seminal vesicles

Resolution:

3.20Å

R-factor:

0.218

R-free:

0.248

Authors:

P.J.Loll,C.T.Sharkey,S.J.O'Connor,D.J.Fitzgerald

Key ref:

P.J.Loll et al. (2001). O-acetylsalicylhydroxamic acid, a novel acetylating inhibitor of prostaglandin H2 synthase: structural and functional characterization of enzyme-inhibitor interactions. Mol Pharmacol, 60, 1407-1413. PubMed id: 11723249

Date:

24-Jan-00

Release date:

24-Feb-00

PROCHECK

	Headers

	References

Protein chain

P05979 (PGH1_SHEEP) - Prostaglandin G/H synthase 1 from Ovis aries

Seq: Struc:

Seq: Struc:					600 a.a. 551 a.a.*

Key:

PfamA domain

Secondary structure

CATH domain

* PDB and UniProt seqs differ at 3 residue positions (black crosses)



		Enzyme reactions

Enzyme class:

E.C.1.14.99.1 - prostaglandin-endoperoxide synthase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

(5Z,8Z,11Z,14Z)-eicosatetraenoate + AH2 + 2 O2 = prostaglandin H2 + A + H2O

(5Z,8Z,11Z,14Z)-eicosatetraenoate	+	AH2	+	2 × O2	=	prostaglandin H2	+		+	H2O Bound ligand (Het Group name = HEM) matches with 51.11% similarity

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

Added reference

	Mol Pharmacol 60:1407-1413 (2001)
PubMed id: 11723249

O-acetylsalicylhydroxamic acid, a novel acetylating inhibitor of prostaglandin H2 synthase: structural and functional characterization of enzyme-inhibitor interactions.
P.J.Loll, C.T.Sharkey, S.J.O'Connor, C.M.Dooley, E.O'Brien, M.Devocelle, K.B.Nolan, B.S.Selinsky, D.J.Fitzgerald.

ABSTRACT

Aspirin is unique among clinically used nonsteroidal antiinflammatory drugs in that it irreversibly inactivates prostaglandin (PG) H2 synthase (PGHS) via acetylation of an active-site serine residue. We report the synthesis and characterization of a novel acetylating agent, O-acetylsalicylhydroxamic acid (AcSHA), which inhibits PGE2 synthesis in vivo and blocks the cyclooxygenase activity of PGHS in vitro. AcSHA requires the presence of the active-site residue Ser-529 to be active against human PGHS-1; the S529A mutant is resistant to inactivation by the inhibitor. Analysis of PGHS inactivation by AcSHA, coupled with the X-ray crystal structure of the complex of ovine PGHS-1 with AcSHA, confirms that the inhibitor elicits its effects via acetylation of Ser-529 in the cyclooxygenase active site. The crystal structure reveals an intact inhibitor molecule bound in the enzyme's cyclooxygenase active-site channel, hydrogen bonding with Arg-119 of the enzyme. The structure-activity profile of AcSHA can be rationalized in terms of the crystal structure of the enzyme-ligand complex. AcSHA may prove useful as a lead compound to facilitate the development of new acetylating inhibitors.

Literature references that cite this PDB file's key reference

PubMed id

Reference

20196542

R.S.Deeb, C.Cheung, T.Nuriel, B.D.Lamon, R.K.Upmacis, S.S.Gross, and D.P.Hajjar (2010).
Physical evidence for substrate binding in preventing cyclooxygenase inactivation under nitrative stress.

J Am Chem Soc, 132, 3914-3922.

19433337

C.E.Rogge, W.Liu, R.J.Kulmacz, and A.L.Tsai (2009).
Peroxide-induced radical formation at TYR385 and TYR504 in human PGHS-1.

J Inorg Biochem, 103, 912-922.

19326386

M.Scholz, K.Bensdorf, R.Gust, and E.Hey-Hawkins (2009).
Asborin: the carbaborane analogue of aspirin.

ChemMedChem, 4, 746-748.

16211102

J.Lee, A.J.Chubb, E.Moman, B.M.McLoughlin, C.T.Sharkey, J.G.Kelly, K.B.Nolan, M.Devocelle, and D.J.Fitzgerald (2005).
Parallel synthesis and in vitro activity of novel anthranilic hydroxamate-based inhibitors of the prostaglandin H2 synthase peroxidase activity.

Org Biomol Chem, 3, 3678-3685.

17191953

R.G.Huff, E.Bayram, H.Tan, S.T.Knutson, M.H.Knaggs, A.B.Richon, P.Santago, and J.S.Fetrow (2005).
Chemical and structural diversity in cyclooxygenase protein active sites.

Chem Biodivers, 2, 1533-1552.

15289285

D.Taubert, R.Berkels, N.Grosser, H.Schröder, D.Gründemann, and E.Schömig (2004).
Aspirin induces nitric oxide release from vascular endothelium: a novel mechanism of action.

Br J Pharmacol, 143, 159-165.

12574066

R.M.Garavito, and A.M.Mulichak (2003).
The structure of mammalian cyclooxygenases.

Annu Rev Biophys Biomol Struct, 32, 183-206.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.