1PTH

The Structural Basis of Aspirin Activity Inferred from the Crystal Structure of Inactivated Prostaglandin H2 Synthase

PDB DOI: https://doi.org/10.2210/pdb1PTH/pdb

Classification: OXIDOREDUCTASE
Organism(s): Ovis aries
Mutation(s): No
Membrane Protein: Yes mpstruc

Deposited: 1995-04-11 Released: 1996-04-11
Deposition Author(s): Loll, P.J., Picot, D., Garavito, R.M.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 3.40 ?
R-Value Free:
0.227 (Depositor)
R-Value Work:
0.186 (Depositor)
R-Value Observed:
0.186 (Depositor)

wwPDB Validation 3D Report Full Report

This is version 2.0 of the entry. See complete history.

Literature

The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H2 synthase.

Loll, P.J., Picot, D., Garavito, R.M.

(1995) Nat Struct Biol 2: 637-643

PubMed: 7552725 Search on PubMed
DOI: https://doi.org/10.1038/nsb0895-637
Primary Citation of Related Structures:
1PTH

PubMed Abstract:
Aspirin exerts its anti-inflammatory effects through selective acetylation of serine 530 on prostaglandin H2 synthase (PGHS). Here we present the 3.4 A resolution X-ray crystal structure of PGHS isoform-1 inactivated by the potent aspirin analogue 2-bromoacetoxy-benzoic acid. Acetylation by this analogue abolishes cyclooxygenase activity by steric blockage of the active-site channel and not through a large conformational change. We observe two rotameric states of the acetyl-serine side chain which block the channel to different extents, a result which may explain the dissimilar effects of aspirin on the two PGHS isoforms. We also observe the product salicylic acid binding at a site consistent with its antagonistic effect on aspirin activity.

Organizational Affiliation

Department of Biochemistry and Molecular Biology, University of Chicago, Illinois 60637, USA.

Macromolecule Content

Total Structure Weight: 136.4 kDa
Atom Count: 9,221
Modelled Residue Count: 1,102
Deposited Residue Count: 1,152
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
PROSTAGLANDIN H2 SYNTHASE-1	A, B	576	Ovis aries	Mutation(s): 0 EC: 1.14.99.1 Membrane Entity: Yes
UniProt
Find proteins for P05979 (Ovis aries) Explore P05979 Go to UniProtKB: P05979
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P05979
Glycosylation
Glycosylation Sites: 3	Glycosylation Focus chain A Focus chain B
Sequence Annotations Expand
Reference Sequence

Oligosaccharides

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Entity ID: 2
Molecule	Chains	Length	2D Diagram	Glycosylation	3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose	C, D	2		N-Glycosylation	Interactions Focus chain C Focus chain D
Glycosylation Resources
GlyTouCan: G42666HT GlyCosmos: G42666HT GlyGen: G42666HT

Small Molecules

Ligands 4 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
HEM Query on HEM Download Ideal Coordinates CCD File SDF format, chain M [auth B] SDF format, chain H [auth A] MOL2 format, chain M [auth B] MOL2 format, chain H [auth A] mmCIF format, chain M [auth B] mmCIF format, chain H [auth A]	H [auth A], M [auth B]	PROTOPORPHYRIN IX CONTAINING FE C₃₄ H₃₂ Fe N₄ O₄ KABFMIBPWCXCRK-RGGAHWMASA-L		Interactions Focus chain H [auth A] Focus chain M [auth B]
BOG Query on BOG Download Ideal Coordinates CCD File SDF format, chain G [auth A] SDF format, chain L [auth B] MOL2 format, chain G [auth A] MOL2 format, chain L [auth B] mmCIF format, chain G [auth A] mmCIF format, chain L [auth B]	G [auth A], L [auth B]	octyl beta-D-glucopyranoside C₁₄ H₂₈ O₆ HEGSGKPQLMEBJL-RKQHYHRCSA-N		Interactions Focus chain G [auth A] Focus chain L [auth B]
NAG Query on NAG Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain F [auth A] SDF format, chain J [auth B] SDF format, chain K [auth B] MOL2 format, chain E [auth A] MOL2 format, chain F [auth A] MOL2 format, chain J [auth B] MOL2 format, chain K [auth B] mmCIF format, chain E [auth A] mmCIF format, chain F [auth A] mmCIF format, chain J [auth B] mmCIF format, chain K [auth B]	E [auth A], F [auth A], J [auth B], K [auth B]	2-acetamido-2-deoxy-beta-D-glucopyranose C₈ H₁₅ N O₆ OVRNDRQMDRJTHS-FMDGEEDCSA-N		Interactions Focus chain E [auth A] Focus chain F [auth A] Focus chain J [auth B] Focus chain K [auth B]
SAL Query on SAL Download Ideal Coordinates CCD File SDF format, chain I [auth A] SDF format, chain N [auth B] MOL2 format, chain I [auth A] MOL2 format, chain N [auth B] mmCIF format, chain I [auth A] mmCIF format, chain N [auth B]	I [auth A], N [auth B]	2-HYDROXYBENZOIC ACID C₇ H₆ O₃ YGSDEFSMJLZEOE-UHFFFAOYSA-N		Interactions Focus chain I [auth A] Focus chain N [auth B]

Modified Residues 1 Unique
ID	Chains	Type	Formula	2D Diagram	Parent
0AH Query on 0AH	A, B	L-PEPTIDE LINKING	C₅ H₈ Br N O₄		SER

Binding Affinity Annotations
ID	Source	Binding Affinity
SAL	BindingDB: 1PTH	Ki: 1.00e+4 (nM) from 1 assay(s)
SAL	BindingDB: 1PTH	IC50: min: 4.00e+4, max: 5.00e+5 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 3.40 ?
R-Value Free: 0.227 (Depositor)
R-Value Work: 0.186 (Depositor)
R-Value Observed: 0.186 (Depositor)

Space Group: I 2 2 2

Unit Cell:

Length ( ? )	Angle ( ? )
a = 99.57	α = 90
b = 209.8	β = 90
c = 235	γ = 90

Software Package:

Software Name	Purpose
MADNES	data collection
X-PLOR	model building
X-PLOR	refinement
MADNES	data reduction
X-PLOR	phasing

Structure Validation

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Entry History

Deposition Data

Released Date: 1996-04-11

Deposition Author(s):

Loll, P.J.

Picot, D.

Garavito, R.M.

Revision History (Full details and data files)

Version 1.0: 1996-04-11
Type: Initial release
Version 1.1: 2008-03-03
Changes: Version format compliance
Version 1.2: 2011-07-13
Changes: Non-polymer description, Version format compliance
Version 2.0: 2020-07-29
Type: Remediation
Reason: Carbohydrate remediation
Changes: Atomic model, Data collection, Derived calculations, Other, Structure summary