دورية أكاديمية
أعرض في EDS

Massive antibody discovery used to probe structure-function relationships of the essential outer membrane protein LptD.

التفاصيل البيبلوغرافية
العنوان: Massive antibody discovery used to probe structure-function relationships of the essential outer membrane protein LptD.
المؤلفون: Storek KM; Department of Infectious Diseases, Genentech, Inc, South San Francisco, United States., Chan J; Department of Biochemical and Cellular Pharmacology, Genentech, Inc, South San Francisco, United States., Vij R; Department of Antibody Engineering, Genentech, Inc, South San Francisco, United States., Chiang N; Department of Antibody Engineering, Genentech, Inc, South San Francisco, United States., Lin Z; Department of Antibody Engineering, Genentech, Inc, South San Francisco, United States., Bevers J 3rd; Department of Antibody Engineering, Genentech, Inc, South San Francisco, United States., Koth CM; Department of Structural Biology, Genentech, Inc, South San Francisco, United States., Vernes JM; Department of Biochemical and Cellular Pharmacology, Genentech, Inc, South San Francisco, United States., Meng YG; Department of Biochemical and Cellular Pharmacology, Genentech, Inc, South San Francisco, United States., Yin J; Department of Structural Biology, Genentech, Inc, South San Francisco, United States., Wallweber H; Department of Structural Biology, Genentech, Inc, South San Francisco, United States., Dalmas O; Department of Structural Biology, Genentech, Inc, South San Francisco, United States., Shriver S; Department of Biomolecular Resources, Genentech, Inc, South San Francisco, United States., Tam C; Department of Biomolecular Resources, Genentech, Inc, South San Francisco, United States., Schneider K; Department of Antibody Engineering, Genentech, Inc, South San Francisco, United States., Seshasayee D; Department of Antibody Engineering, Genentech, Inc, South San Francisco, United States., Nakamura G; Department of Antibody Engineering, Genentech, Inc, South San Francisco, United States., Smith PA; Department of Infectious Diseases, Genentech, Inc, South San Francisco, United States., Payandeh J; Department of Structural Biology, Genentech, Inc, South San Francisco, United States., Koerber JT; Department of Antibody Engineering, Genentech, Inc, South San Francisco, United States., Comps-Agrar L; Department of Biochemical and Cellular Pharmacology, Genentech, Inc, South San Francisco, United States., Rutherford ST; Department of Infectious Diseases, Genentech, Inc, South San Francisco, United States.
المصدر: ELife [Elife] 2019 Jun 25; Vol. 8. Date of Electronic Publication: 2019 Jun 25.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: eLife Sciences Publications, Ltd Country of Publication: England NLM ID: 101579614 Publication Model: Electronic Cited Medium: Internet ISSN: 2050-084X (Electronic) Linking ISSN: 2050084X NLM ISO Abbreviation: Elife Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Cambridge, UK : eLife Sciences Publications, Ltd., 2012-
مواضيع طبية MeSH: Antibodies, Monoclonal/*metabolism , Bacterial Outer Membrane Proteins/*chemistry , Bacterial Outer Membrane Proteins/*metabolism , Escherichia coli Proteins/*chemistry , Escherichia coli Proteins/*metabolism, Animals ; Anti-Bacterial Agents/pharmacology ; Binding Sites ; Epitope Mapping ; Epitopes/metabolism ; Escherichia coli/growth & development ; Escherichia coli/metabolism ; Mice, Inbred BALB C ; Protein Structure, Secondary ; Rats, Sprague-Dawley ; Structure-Activity Relationship
مستخلص: Outer membrane proteins (OMPs) in Gram-negative bacteria dictate permeability of metabolites, antibiotics, and toxins. Elucidating the structure-function relationships governing OMPs within native membrane environments remains challenging. We constructed a diverse library of >3000 monoclonal antibodies to assess the roles of extracellular loops (ECLs) in LptD, an essential OMP that inserts lipopolysaccharide into the outer membrane of Escherichia coli . Epitope binning and mapping experiments with LptD-loop-deletion mutants demonstrated that 7 of the 13 ECLs are targeted by antibodies. Only ECLs inaccessible to antibodies were required for the structure or function of LptD. Our results suggest that antibody-accessible loops evolved to protect key extracellular regions of LptD, but are themselves dispensable. Supporting this hypothesis, no α-LptD antibody interfered with essential functions of LptD. Our experimental workflow enables structure-function studies of OMPs in native cellular environments, provides unexpected insight into LptD, and presents a method to assess the therapeutic potential of antibody targeting.
Competing Interests: KS, JC, RV, NC, ZL, JB, CK, JV, YM, JY, HW, OD, SS, CT, KS, DS, GN, PS, JP, JK, LC, SR Employee of Genentech, Inc, a member of the Roche Group, and shareholder in Roche.
(© 2019, Storek et al.)
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فهرسة مساهمة: Keywords: E. coli; K. pneumoniae; LPS; LptD; infectious disease; microbiology; molecular biophysics; monoclonal antibodies; outer membrane; structural biology
المشرفين على المادة: 0 (Anti-Bacterial Agents)
0 (Antibodies, Monoclonal)
0 (Bacterial Outer Membrane Proteins)
0 (Epitopes)
0 (Escherichia coli Proteins)
0 (LptD protein, E coli)
تواريخ الأحداث: Date Created: 20190626 Date Completed: 20200219 Latest Revision: 20200309
رمز التحديث: 20240628
مُعرف محوري في PubMed: PMC6592684
DOI: 10.7554/eLife.46258
PMID: 31237236
قاعدة البيانات: MEDLINE
الوصف
تدمد:2050-084X
DOI:10.7554/eLife.46258