Location of Inhibitor Binding Sites in the Human Inducible Prostaglandin E Synthase, MPGES1

Prage, Edward B.; Pawelzik, Sven-Christian; Busenlehner, Laura S.; Kim, Kwang‐Ho; Morgenstern, Ralf; Jakobsson, Per‐Johan; Armstrong, Richard N.

doi:10.1021/bi2010448

Cited by 33 publications

(35 citation statements)

References 29 publications

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“…2C), illustrating the scope for exploring polar interaction in this area. Inhibitor binding to the active site is supported by recent hydrogen/deuterium exchange kinetics experiments, indicating changes in exchange rates in the mPGES-1 peptide consisting of residues 37-54 upon binding of potent inhibitors (25). Because the active site is very shallow, orthosteric inhibition is likely to imply residues outside the catalytic cavity also.…”

Section: Discussionmentioning

confidence: 90%

Crystal structure of microsomal prostaglandin E₂synthase provides insight into diversity in the MAPEG superfamily

Sjögren

Nord

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

139

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Prostaglandin E 2 (PGE 2 ) is a key mediator in inflammatory response. The main source of inducible PGE 2 , microsomal PGE 2 synthase-1 (mPGES-1), has emerged as an interesting drug target for treatment of pain. To support inhibitor design, we have determined the crystal structure of human mPGES-1 to 1.2 Å resolution. The structure reveals three well-defined active site cavities within the membrane-spanning region in each monomer interface of the trimeric structure. An important determinant of the active site cavity is a small cytosolic domain inserted between transmembrane helices I and II. This extra domain is not observed in other structures of proteins within the MAPEG (MembraneAssociated Proteins involved in Eicosanoid and Glutathione metabolism) superfamily but is likely to be present also in microsomal GST-1 based on sequence similarity. An unexpected feature of the structure is a 16-Å-deep cone-shaped cavity extending from the cytosolic side into the membrane-spanning region. We suggest a potential role for this cavity in substrate access. Based on the structure of the active site, we propose a catalytic mechanism in which serine 127 plays a key role. We have also determined the structure of mPGES-1 in complex with a glutathione-based analog, providing insight into mPGES-1 flexibility and potential for structure-based drug design.membrane protein | X-ray crystallography | enzyme mechanism P rostaglandins are potent lipid messengers and are involved in numerous homeostatic biological functions [for a review of eicosanoid biology, see review by C. D. Funk (1)]. They are enzymatically derived from the essential fatty acid arachidonic acid and the synthesis proceeds via the formation of prostaglandin H 2 (PGH 2 ), a reaction catalyzed by the constitutively active cyclooxygenase COX-1 and the inducible cyclooxygenase COX-2. PGH 2 acts as a substrate for a range of terminal prostaglandin synthases, including the PGE synthases (PGES, EC 5.3.99.3) that convert PGH 2 to PGE 2 .Microsomal prostaglandin E 2 synthase-1 (mPGES-1), colocalized and up-regulated in concert with COX-2, is the major source of inducible PGE 2 and is associated with inflammation and pain (2). Several studies support a role for mPGES-1 also in cancer cell proliferation and tumor growth (3). Because treatment with COX-2 selective inhibitors is associated with elevated cardiovascular risk, safer approaches involving, for example, PGE 2 reduction, are needed (4). Mice deficient in mPGES-1 have shown significantly reduced effect on hypertension, thrombosis, and myocardial damage compared with inhibition or disruption of COX-2, suggesting mPGES-1 to be a potential target for pharmaceutical intervention in various areas of diseases (2, 5).mPGES-1 belongs to a superfamily of Membrane-Associated Proteins involved in Eicosanoid and Glutathione metabolism, the MAPEG family (6). Members of the MAPEG family can be found in prokaryotes and eukaryotes but not in archaea (7). The most closely related MAPEG member is the microsomal glutathione transferase-1...

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Section: Discussionmentioning

confidence: 90%

Crystal structure of microsomal prostaglandin E₂synthase provides insight into diversity in the MAPEG superfamily

Sjögren

Nord

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

139

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“…MGST1 has high sequence homology to prostaglandin E synthase ( MGST1L1 ), another homologue of the MAPEG family that shares 38% of its DNA sequences with MGST1 . 16 MGST1 and MGST1L1 are upregulated in several cancers, including colorectal cancer. 17,18 MGST1L1 is coexpressed and functionally coupled to prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2), and the combined activity of MGST1L1 and COX-2 increases production of proinflammatory prostaglandin E 2 (PGE 2 ), which promotes carcinogenesis through several mechanisms, including stimulation of WNT signaling, an essential oncogenic pathway of colorectal cancer.…”

Section: Discussionmentioning

confidence: 99%

Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants

Nan

Hutter

Lin

et al. 2015

JAMA

181

108

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IMPORTANCE Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.OBJECTIVE To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer. DESIGN, SETTING, AND PARTICIPANTSCase-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent.EXPOSURES Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors. MAIN OUTCOMES AND MEASURES Colorectal cancer.RESULTS Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10 −28 ) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10 −9 for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10 −33 ) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10 −9 for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10 −30 ) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76). CONCLUSIONS AND RELEVANCEIn this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.

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“…Hydrogen/deuterium exchange kinetics experiments suggest that potent inhibitors of mPGES-1 bind to the active site [37]. Allosteric inhibitors of mPGES-1 have not been described so far.…”

Section: Mechanismmentioning

confidence: 99%

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

Koeberle

Werz

2015

Biochemical Pharmacology

112

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Location of Inhibitor Binding Sites in the Human Inducible Prostaglandin E Synthase, MPGES1

Cited by 33 publications

References 29 publications

Crystal structure of microsomal prostaglandin E₂synthase provides insight into diversity in the MAPEG superfamily

Crystal structure of microsomal prostaglandin E₂synthase provides insight into diversity in the MAPEG superfamily

Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

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Location of Inhibitor Binding Sites in the Human Inducible Prostaglandin E Synthase, MPGES1

Cited by 33 publications

References 29 publications

Crystal structure of microsomal prostaglandin E2synthase provides insight into diversity in the MAPEG superfamily

Crystal structure of microsomal prostaglandin E2synthase provides insight into diversity in the MAPEG superfamily

Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants

Perspective of microsomal prostaglandin E2 synthase-1 as drug target in inflammation-related disorders

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Crystal structure of microsomal prostaglandin E₂synthase provides insight into diversity in the MAPEG superfamily

Crystal structure of microsomal prostaglandin E₂synthase provides insight into diversity in the MAPEG superfamily