6w2l

Crystal structure of human dehydrodolichyl diphosphate synthase (NgBR/DHDDS) in complex with Mg and IPPCrystal structure of human dehydrodolichyl diphosphate synthase (NgBR/DHDDS) in complex with Mg and IPP

Structural highlights

6w2l is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.306Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

DHDDS_HUMAN Non-specific early-onset epileptic encephalopathy;Retinitis pigmentosa. The disease is caused by variants affecting the gene represented in this entry. The disease may be caused by variants affecting the gene represented in this entry.

Function

DHDDS_HUMAN With NUS1, forms the dehydrodolichyl diphosphate synthase (DDS) complex, an essential component of the dolichol monophosphate (Dol-P) biosynthetic machinery. Both subunits contribute to enzymatic activity, i.e. condensation of multiple copies of isopentenyl pyrophosphate (IPP) to farnesyl pyrophosphate (FPP) to produce dehydrodolichyl diphosphate (Dedol-PP), a precursor of dolichol phosphate which is utilized as a sugar carrier in protein glycosylation in the endoplasmic reticulum (ER) (PubMed:25066056, PubMed:28842490, PubMed:32817466). Synthesizes long-chain polyprenols, mostly of C95 and C100 chain length (PubMed:32817466). Regulates the glycosylation and stability of nascent NPC2, thereby promoting trafficking of LDL-derived cholesterol (PubMed:21572394).^[1] ^[2] ^[3] ^[4]

Publication Abstract from PubMed

Cis-prenyltransferase (cis-PTase) catalyzes the rate-limiting step in the synthesis of glycosyl carrier lipids required for protein glycosylation in the lumen of endoplasmic reticulum. Here, we report the crystal structure of the human NgBR/DHDDS complex, which represents an atomic resolution structure for any heterodimeric cis-PTase. The crystal structure sheds light on how NgBR stabilizes DHDDS through dimerization, participates in the enzyme's active site through its C-terminal -RXG- motif, and how phospholipids markedly stimulate cis-PTase activity. Comparison of NgBR/DHDDS with homodimeric cis-PTase structures leads to a model where the elongating isoprene chain extends beyond the enzyme's active site tunnel, and an insert within the alpha3 helix helps to stabilize this energetically unfavorable state to enable long-chain synthesis to occur. These data provide unique insights into how heterodimeric cis-PTases have evolved from their ancestral, homodimeric forms to fulfill their function in long-chain polyprenol synthesis.

Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation.,Edani BH, Grabinska KA, Zhang R, Park EJ, Siciliano B, Surmacz L, Ha Y, Sessa WC Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20794-20802. doi:, 10.1073/pnas.2008381117. Epub 2020 Aug 12. PMID:32817466^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Harrison KD, Park EJ, Gao N, Kuo A, Rush JS, Waechter CJ, Lehrman MA, Sessa WC. Nogo-B receptor is necessary for cellular dolichol biosynthesis and protein N-glycosylation. EMBO J. 2011 May 13;30(12):2490-500. PMID:21572394 doi:10.1038/emboj.2011.147
↑ Park EJ, Grabinska KA, Guan Z, Stranecky V, Hartmannova H, Hodanova K, Baresova V, Sovova J, Jozsef L, Ondruskova N, Hansikova H, Honzik T, Zeman J, Hulkova H, Wen R, Kmoch S, Sessa WC. Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a congenital disorder of glycosylation. Cell Metab. 2014 Sep 2;20(3):448-57. doi: 10.1016/j.cmet.2014.06.016. Epub 2014, Jul 24. PMID:25066056 doi:http://dx.doi.org/10.1016/j.cmet.2014.06.016
↑ Grabińska KA, Edani BH, Park EJ, Kraehling JR, Sessa WC. A conserved C-terminal RXG motif in the NgBR subunit of cis-prenyltransferase is critical for prenyltransferase activity. J Biol Chem. 2017 Oct 20;292(42):17351-17361. PMID:28842490 doi:10.1074/jbc.M117.806034
↑ Edani BH, Grabińska KA, Zhang R, Park EJ, Siciliano B, Surmacz L, Ha Y, Sessa WC. Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation. Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20794-20802. PMID:32817466 doi:10.1073/pnas.2008381117
↑ Edani BH, Grabińska KA, Zhang R, Park EJ, Siciliano B, Surmacz L, Ha Y, Sessa WC. Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation. Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20794-20802. PMID:32817466 doi:10.1073/pnas.2008381117

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OCA

[1] Harrison KD, Park EJ, Gao N, Kuo A, Rush JS, Waechter CJ, Lehrman MA, Sessa WC. Nogo-B receptor is necessary for cellular dolichol biosynthesis and protein N-glycosylation. EMBO J. 2011 May 13;30(12):2490-500. PMID:21572394 doi:10.1038/emboj.2011.147

[2] Park EJ, Grabinska KA, Guan Z, Stranecky V, Hartmannova H, Hodanova K, Baresova V, Sovova J, Jozsef L, Ondruskova N, Hansikova H, Honzik T, Zeman J, Hulkova H, Wen R, Kmoch S, Sessa WC. Mutation of Nogo-B receptor, a subunit of cis-prenyltransferase, causes a congenital disorder of glycosylation. Cell Metab. 2014 Sep 2;20(3):448-57. doi: 10.1016/j.cmet.2014.06.016. Epub 2014, Jul 24. PMID:25066056 doi:http://dx.doi.org/10.1016/j.cmet.2014.06.016

[3] Grabińska KA, Edani BH, Park EJ, Kraehling JR, Sessa WC. A conserved C-terminal RXG motif in the NgBR subunit of cis-prenyltransferase is critical for prenyltransferase activity. J Biol Chem. 2017 Oct 20;292(42):17351-17361. PMID:28842490 doi:10.1074/jbc.M117.806034

[4] Edani BH, Grabińska KA, Zhang R, Park EJ, Siciliano B, Surmacz L, Ha Y, Sessa WC. Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation. Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20794-20802. PMID:32817466 doi:10.1073/pnas.2008381117

[5] Edani BH, Grabińska KA, Zhang R, Park EJ, Siciliano B, Surmacz L, Ha Y, Sessa WC. Structural elucidation of the cis-prenyltransferase NgBR/DHDDS complex reveals insights in regulation of protein glycosylation. Proc Natl Acad Sci U S A. 2020 Aug 25;117(34):20794-20802. PMID:32817466 doi:10.1073/pnas.2008381117

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