O-GlcNAcase
From Proteopedia
(Difference between revisions)
(New page: <StructureSection load='1stp' size='340' side='right' caption='Caption for this structure' scene=''> describing Jmol <ref>PMID:21638687</ref> to the rescue. == Function == '''O-GlcNAcas...) |
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| - | <StructureSection load=' | + | <StructureSection load='5m7s' size='400' side='right' caption='Human OGA complex with transition state analog (PDB code [[5m7s]]' scene='86/863205/Cv/2'> |
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== Function == | == Function == | ||
| - | '''O-GlcNAcase''' or '''hyaluronoglucosaminidase''' (OGA) | + | '''O-GlcNAcase''' or '''hyaluronoglucosaminidase''' (OGA) is one of two enzymes which modulate the level of O-linked N-acetylglucosamine (O-GlcNAc) attachment to cytoplasmic, nuclear and mitochondrial proteins<ref>PMID:22311971</ref>. The attachment of O-GlcNAc to proteins is a post-translational modification. |
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== Relevance == | == Relevance == | ||
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| + | Inhibition of OGA is a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy<ref>PMID:31487175</ref>. The inhibition of OGA hinders formation of tau aggregates and decreases neuronal cell loss<ref>PMID:22366723</ref>. | ||
== Structural highlights == | == Structural highlights == | ||
| + | The 3D structure of the complex between human OGA and a transition state analog Thiamet-G shows the active site pocket at the base of a V-shaped cleft between the 2 OGA monomers. There are <scene name='86/863205/Cv/8'>numerous H-bonds</scene> formed between OGA and Thiamet-G as well as some <scene name='86/863205/Cv/9'>hydrophobic interactions</scene>. <scene name='86/863205/Cv/11'>Two Asp residues</scene> are defined as catalytic residues<ref>PMID:28346405</ref>. | ||
</StructureSection> | </StructureSection> | ||
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**[[5m7t]] - hOGA + PUGNAc derivative<br /> | **[[5m7t]] - hOGA + PUGNAc derivative<br /> | ||
**[[5uho]] - hOGA TIM barrel and stalk domains + PUGNAc<br /> | **[[5uho]] - hOGA TIM barrel and stalk domains + PUGNAc<br /> | ||
| + | **[[5mi6]] - hOGA + transition state analog + inhibitor<br /> | ||
**[[2j62]] - CpOGA + GlcNAcstatin<br /> | **[[2j62]] - CpOGA + GlcNAcstatin<br /> | ||
**[[2wb5]], [[2x0y]], [[2xpk]], [[5oxd]] - CpOGA + inhibitor<br /> | **[[2wb5]], [[2x0y]], [[2xpk]], [[5oxd]] - CpOGA + inhibitor<br /> | ||
| + | **[[7khv]] - CpOGA (mutant) + pyrimidine derivative<br /> | ||
**[[2vvs]], [[2wca]] - BtOGA + PUGNAc<br /> | **[[2vvs]], [[2wca]] - BtOGA + PUGNAc<br /> | ||
| - | [[2j4g]], [[2w4x]], [[2vvn]], [[2w66]], [[2w67]], [[2xj7]], [[2xm1]], [[4aiu]], [[4ais]], [[2wzi]], [[2wzh]], [[4ur9]], [[5fky]], [[5fl0]], [[5fl1]] - BtOGA + inhibitor<br /> | + | **[[2j4g]], [[2w4x]], [[2vvn]], [[2w66]], [[2w67]], [[2xj7]], [[2xm1]], [[4aiu]], [[4ais]], [[2wzi]], [[2wzh]], [[4ur9]], [[5fky]], [[5fl0]], [[5fl1]], [[7ou6]], [[7ou8]] - BtOGA + inhibitor<br /> |
**[[5mi4]] - BtOGA (mutant) + inhibitor<br /> | **[[5mi4]] - BtOGA (mutant) + inhibitor<br /> | ||
**[[2xm2]] - BtOGA + LOGNAc<br /> | **[[2xm2]] - BtOGA + LOGNAc<br /> | ||
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**[[5mi5]], [[5mi7]] - BtOGA + PUGNAc + inhibitor<br /> | **[[5mi5]], [[5mi7]] - BtOGA + PUGNAc + inhibitor<br /> | ||
**[[2x0h]] - BtOGA + michaelis complex<br /> | **[[2x0h]] - BtOGA + michaelis complex<br /> | ||
| - | **[[5mi6]] - hOGA + transition state analog + inhibitor<br /> | ||
**[[2xsb]] - OgOGA + PUGNAc<br /> | **[[2xsb]] - OgOGA + PUGNAc<br /> | ||
| + | **[[7khs]] - OgOGA catalytic domain 1-447 + pyrimidine derivative<br /> | ||
| + | **[[7k41]] - EcOGA + inhibitor – ''Escherichia coli''<br /> | ||
*O-GlcNAcase complex with polypeptide | *O-GlcNAcase complex with polypeptide | ||
**[[5vvx]], [[5vvt]], [[5vvv]], [[5vvu]], [[5un8]] - hOGA TIM barrel and stalk domains + peptide + NAG<br /> | **[[5vvx]], [[5vvt]], [[5vvv]], [[5vvu]], [[5un8]] - hOGA TIM barrel and stalk domains + peptide + NAG<br /> | ||
| + | **[[7yeh]] - hOGA 1-916 + OGT + NAG + UDP<br /> | ||
**[[2yds]], [[2ydq]], [[4zxl]], [[6rhe]], [[2ydr]] - CpOGA (mutant) + peptide<br /> | **[[2yds]], [[2ydq]], [[4zxl]], [[6rhe]], [[2ydr]] - CpOGA (mutant) + peptide<br /> | ||
**[[2ozn]] - CpOGA cohesin domain + hyaluronidase dockerin domain<br /> | **[[2ozn]] - CpOGA cohesin domain + hyaluronidase dockerin domain<br /> | ||
Current revision
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3D structures of O-GlcNAcase
Updated on 17-August-2023
References
- ↑ Shen DL, Gloster TM, Yuzwa SA, Vocadlo DJ. Insights into O-linked N-acetylglucosamine ([0-9]O-GlcNAc) processing and dynamics through kinetic analysis of O-GlcNAc transferase and O-GlcNAcase activity on protein substrates. J Biol Chem. 2012 May 4;287(19):15395-408. doi: 10.1074/jbc.M111.310664. Epub, 2012 Feb 6. PMID:22311971 doi:http://dx.doi.org/10.1074/jbc.M111.310664
- ↑ Selnick HG, Hess JF, Tang C, Liu K, Schachter JB, Ballard JE, Marcus J, Klein DJ, Wang X, Pearson M, Savage MJ, Kaul R, Li TS, Vocadlo DJ, Zhou Y, Zhu Y, Mu C, Wang Y, Wei Z, Bai C, Duffy JL, McEachern EJ. Discovery of MK-8719, a Potent O-GlcNAcase Inhibitor as a Potential Treatment for Tauopathies. J Med Chem. 2019 Nov 27;62(22):10062-10097. doi: 10.1021/acs.jmedchem.9b01090., Epub 2019 Sep 29. PMID:31487175 doi:http://dx.doi.org/10.1021/acs.jmedchem.9b01090
- ↑ Yuzwa SA, Shan X, Macauley MS, Clark T, Skorobogatko Y, Vosseller K, Vocadlo DJ. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat Chem Biol. 2012 Feb 26;8(4):393-9. doi: 10.1038/nchembio.797. PMID:22366723 doi:http://dx.doi.org/10.1038/nchembio.797
- ↑ Roth C, Chan S, Offen WA, Hemsworth GR, Willems LI, King DT, Varghese V, Britton R, Vocadlo DJ, Davies GJ. Structural and functional insight into human O-GlcNAcase. Nat Chem Biol. 2017 Mar 27. doi: 10.1038/nchembio.2358. PMID:28346405 doi:http://dx.doi.org/10.1038/nchembio.2358
