Structural modeling of sequence specificity by an autoantibody against single-stranded DNA.

Structural modeling of sequence specificity by an autoantibody against single-stranded DNA. Research Abstract Details 

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Structural modeling of sequence specificity by an autoantibody against single-stranded DNA. Abstract Text:

Melissa J Bobeck,David Rueda,Nils G Walter,Gary D Glick,

11F8 is a sequence-specific pathogenic anti-single-stranded (ss)DNA autoantibody isolated from a lupus prone mouse. Site-directed mutagenesis of 11F8 has shown that six binding site residues (R31VH, W33VH, L97VH, R98VH, Y100VH, and Y32VL) contribute 80% of the free energy for complex formation. Mutagenesis results along with intermolecular distances obtained from fluorescence resonance energy transfer were implemented here as restraints to model docking between 11F8 and the sequence-specific ssDNA. The model of the complex suggests that aromatic stacking and two sets of bidentate hydrogen bonds between binding site arginine residues (R31VH and R96VH) and loop nucleotides provide the molecular basis for high affinity and specificity. In part, 11F8 utilizes the same ssDNA binding motif of Y32VL, H91VL, and an aromatic residue in the third complementarity-determining region to recognize thymine-rich sequences as do two anti-ssDNA autoantibodies crystallized in complex with thymine. R31SVH is a dominant somatic mutation found in the J558 germline sequence that is implicated in 11F8 sequence specificity. A model of the mutant R31S11F8.ssDNA complex suggests that different interface contacts occur when serine replaces arginine 31 at the binding site. The modeled contacts between the R31S11F8 mutant and thymine are closely related to those observed in other anti-ssDNA binding antibodies, while we find additional contacts between 11F8 and ssDNA that involve amino acids not utilized by the other antibodies. These data-driven 11F8.ssDNA models provide testable hypotheses concerning interactions that mediate sequence specificity in 11F8 and the effects of somatic mutation on ssDNA recognition.

Structural modeling of sequence specificity by an autoantibody against single-stranded DNA. Publishing Authors By Initials

MJ Bobeck,D Rueda,NG Walter,GD Glick,

For similar natural sciences: physics: thermodynamics research abstracts see: natural sciences: physics: thermodynamics research

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Structural modeling of sequence specificity by an autoantibody against single-stranded DNA. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Biochemistry

VOLUME: 46

Page Numbers: 6753-65

Journal Abbreviation: Biochemistry

ISSN: 0006-2960

DAY: 16

MONTH: 05

YEAR: 2007

Structural modeling of sequence specificity by an autoantibody against single-stranded DNA. Information

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LANGUAGE: eng

NlmUniqueID: 370623

Structural modeling of sequence specificity by an autoantibody against single-stranded DNA. Keywords Mesh Terms:

KEYWORDS: Thermodynamics

MESH TERMS: immunology

Chemical & Substance for Abstract: Structural modeling of sequence specificity by an autoantibody against single-stranded DNA. Information

Substance Name: Ligands

Registry Number: 0

Grant and Affiliation Information for Structural modeling of sequence specificity by an autoantibody against single-stranded DNA.

AFFILIATION: Department of Chemistry, University of Michigan, Ann Arbor, Michigan 48109-1055, USA.

Country: United States

AGENCY: United States NIGMS

GRANT: GM 42168

ACRONYM: GM

MEDLINETA: Biochemistry

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