A type III complement factor D deficiency: Structural insights for inhibition of the alternative pathway
Conversely, in both mutant simulations, the distance remained larger, consistent with His41 pointing away from the active site. [...]in addition to disruption of key FB-binding residues, mutations R176P and R176A appear to stabilize the self-inhibited conformation of free FD. Overactivation of AP is...
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| Published in | Journal of allergy and clinical immunology Vol. 142; no. 1; pp. 311 - 314.e6 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
Elsevier Inc
01.07.2018
Elsevier Limited Mosby |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0091-6749 1097-6825 1085-8725 1097-6825 |
| DOI | 10.1016/j.jaci.2018.01.048 |
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| Abstract | Conversely, in both mutant simulations, the distance remained larger, consistent with His41 pointing away from the active site. [...]in addition to disruption of key FB-binding residues, mutations R176P and R176A appear to stabilize the self-inhibited conformation of free FD. Overactivation of AP is implicated in numerous inflammatory disorders, including age-related macular degeneration. [...]blockade of the AP by targeting the rate-limiting enzyme, FD, is an attractive approach to controlling disease progression. Furthermore, circulating concentrations of leptin and adiponectin, adipokines that regulate insulin sensitivity, were normal, as were fasting lipid profiles in both subjects. [...]glucose homeostasis is not impaired in the context of genetic, and therefore lifelong, FD deficiency. [...]research will be required to understand the role of FD in glucose homeostasis and FD-deficient family pedigrees offer a useful clinical insight to this question.Methods Informed consent statement All study participants gave their informed consent as appropriate under approved protocols from local institutional review boards. |
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| AbstractList | Conversely, in both mutant simulations, the distance remained larger, consistent with His41 pointing away from the active site. [...]in addition to disruption of key FB-binding residues, mutations R176P and R176A appear to stabilize the self-inhibited conformation of free FD. Overactivation of AP is implicated in numerous inflammatory disorders, including age-related macular degeneration. [...]blockade of the AP by targeting the rate-limiting enzyme, FD, is an attractive approach to controlling disease progression. Furthermore, circulating concentrations of leptin and adiponectin, adipokines that regulate insulin sensitivity, were normal, as were fasting lipid profiles in both subjects. [...]glucose homeostasis is not impaired in the context of genetic, and therefore lifelong, FD deficiency. [...]research will be required to understand the role of FD in glucose homeostasis and FD-deficient family pedigrees offer a useful clinical insight to this question.Methods Informed consent statement All study participants gave their informed consent as appropriate under approved protocols from local institutional review boards. |
| Author | Thaventhiran, James E.D. Bauer, Matthias R. Challis, Ben G. O'Byrne, Sorcha Ruhle, Michelle Buckland, Matthew S. Semple, Robert K. Modis, Yorgo Sng, Christopher C.T. Magiera, Lukasz Harvey, Jennifer C. Janowitz, Tobias Wilson, Timothy J. Roberts, Lee D. Workman, Sarita Doffinger, Rainer Prigozhin, Daniil M. Jodrell, Duncan J. Lear, Sara |
| AuthorAffiliation | k Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom h Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds Institute of Genetics, Health and Therapeutics (LIGHT) Laboratories, University of Leeds, Leeds, United Kingdom c Molecular Immunity Unit, Department of Medicine, Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge, United Kingdom d Division of Structural Studies, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom l MRC Toxicology Unit, University of Leicester, Leicester, United Kingdom e Department of Immunology, Royal Free London National Health Service Foundation Trust, London, United Kingdom f Walter and Eliza Hall Institute of Medical Research, Parkville, Australia j Department of Microbiology, Miami University, Oxford, Ohio a Cancer Research UK Cambridge Institute, Cambridge, United Kingdom b Department of Clinical Immunology, Cambridge University Hospitals National Health Service Trust, Add |
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| Author_xml | – sequence: 1 givenname: Christopher C.T. orcidid: 0000-0003-2850-1467 surname: Sng fullname: Sng, Christopher C.T. organization: Cancer Research UK Cambridge Institute, Cambridge, United Kingdom – sequence: 2 givenname: Sorcha surname: O'Byrne fullname: O'Byrne, Sorcha organization: Department of Clinical Immunology, Cambridge University Hospitals National Health Service Trust, Addenbrooke's Hospital, Cambridge, United Kingdom – sequence: 3 givenname: Daniil M. orcidid: 0000-0003-2075-0231 surname: Prigozhin fullname: Prigozhin, Daniil M. organization: Molecular Immunity Unit, Department of Medicine, Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge, United Kingdom – sequence: 4 givenname: Matthias R. surname: Bauer fullname: Bauer, Matthias R. organization: Division of Structural Studies, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom – sequence: 5 givenname: Jennifer C. surname: Harvey fullname: Harvey, Jennifer C. organization: Department of Immunology, Royal Free London National Health Service Foundation Trust, London, United Kingdom – sequence: 6 givenname: Michelle surname: Ruhle fullname: Ruhle, Michelle organization: Walter and Eliza Hall Institute of Medical Research, Parkville, Australia – sequence: 7 givenname: Ben G. surname: Challis fullname: Challis, Ben G. organization: Wellcome Trust–MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom – sequence: 8 givenname: Sara surname: Lear fullname: Lear, Sara organization: Department of Clinical Immunology, Cambridge University Hospitals National Health Service Trust, Addenbrooke's Hospital, Cambridge, United Kingdom – sequence: 9 givenname: Lee D. surname: Roberts fullname: Roberts, Lee D. organization: Leeds Institute of Cardiovascular and Metabolic Medicine, Leeds Institute of Genetics, Health and Therapeutics (LIGHT) Laboratories, University of Leeds, Leeds, United Kingdom – sequence: 10 givenname: Sarita surname: Workman fullname: Workman, Sarita organization: Department of Immunology, Royal Free London National Health Service Foundation Trust, London, United Kingdom – sequence: 11 givenname: Tobias orcidid: 0000-0002-7820-3727 surname: Janowitz fullname: Janowitz, Tobias organization: Cancer Research UK Cambridge Institute, Cambridge, United Kingdom – sequence: 12 givenname: Lukasz surname: Magiera fullname: Magiera, Lukasz organization: Cancer Research UK Cambridge Institute, Cambridge, United Kingdom – sequence: 13 givenname: Rainer surname: Doffinger fullname: Doffinger, Rainer organization: Department of Clinical Immunology, Cambridge University Hospitals National Health Service Trust, Addenbrooke's Hospital, Cambridge, United Kingdom – sequence: 14 givenname: Matthew S. orcidid: 0000-0002-5646-4707 surname: Buckland fullname: Buckland, Matthew S. organization: Department of Immunology, Royal Free London National Health Service Foundation Trust, London, United Kingdom – sequence: 15 givenname: Duncan J. surname: Jodrell fullname: Jodrell, Duncan J. organization: Cancer Research UK Cambridge Institute, Cambridge, United Kingdom – sequence: 16 givenname: Robert K. surname: Semple fullname: Semple, Robert K. organization: Wellcome Trust–MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom – sequence: 17 givenname: Timothy J. surname: Wilson fullname: Wilson, Timothy J. organization: Department of Microbiology, Miami University, Oxford, Ohio – sequence: 18 givenname: Yorgo surname: Modis fullname: Modis, Yorgo organization: Molecular Immunity Unit, Department of Medicine, Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge, United Kingdom – sequence: 19 givenname: James E.D. surname: Thaventhiran fullname: Thaventhiran, James E.D. email: jedt2@cam.ac.uk organization: Cancer Research UK Cambridge Institute, Cambridge, United Kingdom |
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| SubjectTerms | Alternative pathway Complement factor D Complement Factor D - chemistry Complement Factor D - deficiency Complement Factor D - genetics Complement Pathway, Alternative Female Hereditary Complement Deficiency Diseases Humans Immunologic Deficiency Syndromes - genetics Inflammatory diseases Macular degeneration Male Metabolism Mutation Pedigree Protein Conformation Simulation Young Adult |
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| Title | A type III complement factor D deficiency: Structural insights for inhibition of the alternative pathway |
| URI | https://www.clinicalkey.com/#!/content/1-s2.0-S0091674918303270 https://dx.doi.org/10.1016/j.jaci.2018.01.048 https://www.ncbi.nlm.nih.gov/pubmed/29522842 https://www.proquest.com/docview/2063219037 https://www.proquest.com/docview/2012911232 https://pubmed.ncbi.nlm.nih.gov/PMC6034011 http://www.jacionline.org/article/S0091674918303270/pdf |
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