Crystal structure of human stearoyl–coenzyme A desaturase in complex with substrate
Abstract
Stearoyl-coenzyme A desaturase-1 (SCD1) has an important role in lipid metabolism, and SCD1 inhibitors are potential therapeutic agents for the treatment of metabolic diseases and cancers. Here we report the 3.25-Å crystal structure of human SCD1 in complex with its substrate, stearoyl-coenzyme A, which defines the new SCD1 dimetal catalytic center and reveals the determinants of substrate binding to provide insights into the catalytic mechanism of desaturation of the stearoyl moiety. The structure also provides a mechanism for localization of SCD1 in the endoplasmic reticulum: human SCD1 folds around a tight hydrophobic core formed from four long α-helices that presumably function as an anchor spanning the endoplasmic reticulum membrane. Furthermore, our results provide a framework for the rational design of pharmacological inhibitors targeting the SCD1 enzyme.
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Superimposing the metal-binding centers of DEGS1 and 4ZYO via the 3-residue templates indicates a potential dimetal catalytic center for DEGS1.
“A close up of the metal-binding center (Fig. 4e) of DEGS1 and 4YZO (overall sequence homology, 12.1%) superimposed via the 3-residue templates (Fig. 4d) clearly indicates the potential dimetal catalytic center for DEGS1.”
From A structural biology community assessment of AlphaFold2 applications (2022) · cites this paper as [39]
A scan of 400 auto-generated 3-residue templates from AF2-predicted DEGS1 against representative PDB structures yielded a possible 3-residue template match to PDB entry 4ZYO (human stearoyl-CoA desaturase).
“A scan of 400 auto-generated 3-residue templates from the AF2-predicted structure against representative structures in the PDB (reverse template comparison38) yielded a possible 3-residue template match: PDB entry 4ZYO (EC 1.14.19.1, human stearoyl-CoA desaturase39, Fig. 4d).”
From A structural biology community assessment of AlphaFold2 applications (2022) · cites this paper as [39]
Cites
[20] Processing of X-ray diffraction data collected in oscillation mode
Otwinowski, Z., & Minor, W. (1997) · Methods in Enzymology · doi:10.1016/s0076-6879(97)76066-x · Cited by 33,475 · see citing works
<i>Coot</i> : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571 · see citing works
<i>PHENIX</i> : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716 · see citing works
The CCP4 suite: programs for protein crystallography
Number Collaborative Computational Project (1994) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444994003112 · Cited by 17,299 · see citing works
Fast, scalable generation of high-quality protein multiple sequence alignments using Clustal Omega
Sievers, F., Wilm, A., Dineen, D., Gibson, T., Karplus, K., Li, W.-Z., Lopez, R., McWilliam, H., Remmert, M., Söding, J., et al. (2011) · Molecular Systems Biology · doi:10.1038/msb.2011.75 · Cited by 15,576 · see citing works
<i>MolProbity</i> : all-atom structure validation for macromolecular crystallography
Chen, V. B., Arendall, W. B., Headd, J. J., Keedy, D. A., Immormino, R. M., Kapral, G. J., Murray, L. W., Richardson, J. S., & Richardson, D. C. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909042073 · Cited by 14,115 · see citing works
Jalview Version 2—a multiple sequence alignment editor and analysis workbench
Waterhouse, A. M., Procter, J. B., Martin, D. M. A., Clamp, M. E., & Barton, G. J. (2009) · Bioinformatics · doi:10.1093/bioinformatics/btp033 · Cited by 10,011 · see citing works
PHENIX: a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkòczi, G., Chen, V. B., Davis, I., Echols, N., Headd, J. J., Hung, L., Kapral, G. J., Grosse‐Kunstleve, R. W., et al. (2012) · International Tables for Crystallography · doi:10.1107/97809553602060000865 · Cited by 7,334 · see citing works
Resolution of phase ambiguity in macromolecular crystallography
Wang, B. (1985) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/0076-6879(85)15009-3 · Cited by 1,033 · see citing works
Three-dimensional structure of the free radical protein of ribonucleotide reductase
Nordlund, P., Sjöberg, B., & Eklund, H. (1990) · Nature · doi:10.1038/345593a0 · Cited by 844 · see citing works
Shanklin, J., Whittle, E. J., & Fox, B. G. (1994) · Biochemistry · doi:10.1021/bi00209a009 · Cited by 764 · see citing works
Enoch, H. G., Catalá, Á., & Strittmatter, P. (1976) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)33223-4 · Cited by 563 · see citing works
Lindqvist, Y., Huang, W., Schneider, G., & Shanklin, J. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb00783.x · Cited by 471 · see citing works
Hulver, M. W., Berggren, J. R., Carper, M. J., Miyazaki, M., Ntambi, J. M., Hoffman, E. P., Thyfault, J. P., Stevens, R., Dohm, G. L., Houmard, J. A., et al. (2005) · Cell Metabolism · doi:10.1016/j.cmet.2005.09.002 · Cited by 384 · see citing works
Attie, A., Krauss, R. M., Gray-Keller, M. P., Brownlie, A., Miyazaki, M., Kastelein, J. J. P., Lusis, A. J., Stalenhoef, A. F. H., Stoehr, J. P., Hayden, M. R., et al. (2002) · Journal of Lipid Research · doi:10.1194/jlr.m200189-jlr200 · Cited by 347 · see citing works
Structural Basis of Biological N 2 O Generation by Bacterial Nitric Oxide Reductase
Hino, T., Matsumoto, Y., Nagano, S., Sugimoto, H., Fukumori, Y., Murata, T., Iwata, S., & Shiro, Y. (2010) · Science · doi:10.1126/science.1195591 · Cited by 330 · see citing works
Rational Protein Crystallization by Mutational Surface Engineering
Derewenda, Z. S. (2004) · Structure · doi:10.1016/j.str.2004.03.008 · Cited by 274 · see citing works
Shanklin, J., Guy, J. E., Mishra, G., & Lindqvist, Y. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.r900009200 · Cited by 201 · see citing works
Sazinsky, M. H., & Lippard, S. J. (2006) · Accounts of Chemical Research · doi:10.1021/ar030204v · Cited by 190 · see citing works
Stearoyl‐CoA desaturase as a new drug target for obesity treatment
Dobrzyń, A., & Ntambi, J. M. (2005) · Obesity Reviews · doi:10.1111/j.1467-789x.2005.00177.x · Cited by 173 · see citing works
Morgan-Lappe, S. E., Tucker, L. A., Huang, X., Zhang, Q., Sarthy, A. V., Zakula, D., Vernetti, L. A., Schurdak, M. E., Wang, J., & Fesik, S. W. (2007) · Cancer Research · doi:10.1158/0008-5472.can-06-4132 · Cited by 130 · see citing works
Crystal structure of quinol-dependent nitric oxide reductase from Geobacillus stearothermophilus
Matsumoto, Y., Tosha, T., Pisliakov, A. V., Hino, T., Sugimoto, H., Nagano, S., Sugita, Y., & Shiro, Y. (2012) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2213 · Cited by 120 · see citing works
Igal, R. A. (2011) · Cancers · doi:10.3390/cancers3022462 · Cited by 103 · see citing works
Stefan, N., Peter, A., Čegan, A., Staiger, H., Machann, J., Schick, F., Claussen, C. D., Fritsche, A., Häring, H., & Schleicher, E. (2008) · Diabetologia · doi:10.1007/s00125-008-0938-7 · Cited by 102 · see citing works
Membrane Topology of Mouse Stearoyl-CoA Desaturase 1
Man, W. C., Miyazaki, M., Chu, K., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m508733200 · Cited by 100 · see citing works
Heilmann, I., Mekhedov, S., King, B., et al. (2004) · PLANT PHYSIOLOGY · doi:10.1104/pp.104.052951 · Cited by 99 · see citing works
Zhang, Z., Dales, N. A., & Winther, M. D. (2013) · Journal of Medicinal Chemistry · doi:10.1021/jm401516c · Cited by 87 · see citing works
Moche, M., Shanklin, J., GHOSHAL, A. K., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m301662200 · Cited by 69 · see citing works
Guy, J. E., Whittle, E. J., Kumaran, D., et al. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m702520200 · Cited by 53 · see citing works
Whittle, E. J., Cahoon, E. B., Subrahmanyam, S., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m504205200 · Cited by 44 · see citing works
Structure and Mechanism of the Diiron Benzoyl-Coenzyme A Epoxidase BoxB
Rather, L. J., Weinert, T., Demmer, U., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m111.236893 · Cited by 32 · see citing works
Stearoyl-CoA desaturase inhibitors: update on patented compounds
Liu, G. (2009) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543770903061311 · Cited by 31 · see citing works
An overview of patented small molecule stearoyl coenzyme-A desaturase inhibitors (2009 – 2013)
Powell, D. A. (2013) · Expert Opinion on Therapeutic Patents · doi:10.1517/13543776.2014.851669 · Cited by 19 · see citing works
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A structural biology community assessment of AlphaFold2 applications
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- Authors
- Wang, H., Klein, M. G., Zou, H., Lane, W., Snell, G., Levin, I., Li, K., & Sang, B.-C.
- Corresponding author
- Wang, Hui
- Klein, Michael G
- Venue
- Nature Structural & Molecular Biology
- Published
- 2015-06-22
- Volume
- 22
- Issue
- 7
- Pages
- 581-585
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- OpenAlex
- W2121593996
- Cited by
- 192
- References
- 33
- Citations by year
- 2026: 6 · 2025: 24 · 2024: 21 · 2023: 15 · 2022: 20 · 2021: 23 · 2020: 26 · 2019: 10 · 2018: 13 · 2017: 14 · 2016: 14 · 2015: 4
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (P50GM082250, GM-105404, R01GM105404, P50GM073210, GM082250, GM094625, GM073210, U54GM094625)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- stearoyl-CoA desaturase 1, unsaturated fatty acid biosynthesis, substrate binding, membrane protein structure, SCD1 inhibitors, lipid metabolism, enzyme mechanism
- MeSH terms
- Acyl Coenzyme A, Binding Sites, Humans, Metals, Models, Molecular, Protein Conformation, Stearoyl-CoA Desaturase, Crystallography, X-Ray
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