Research Mentor(s)

Clint Spiegel

Affiliated Department

Chemistry

Sort Order

46

Start Date

19-5-2016 12:00 PM

End Date

19-5-2016 3:00 PM

Keywords

Factor VIII, hemophilia, structural biology, crystallization, x-ray diffraction

Document Type

Event

Abstract

Factor VIII (fVIII) is a protein that is involved in the coagulation cascade, a collection of reactions that is activated by injury and leads to the formation of blood clots. Deficiencies in fVIII lead to the bleeding disorder hemophilia A, a condition that occurs in 1 in 5000 births. The current treatment for hemophilia A is inefficient and costly; however, there is potential through the use of recombinant hybrid human-porcine fVIII. Hybrid fVIII shows up to 12-fold higher coagulant activity than human fVIII, and can retain its activity even in the presence of inhibitory antibodies. The primary objective of our study is to determine the molecular structure of full-length hybrid human-porcine fVIII through X- ray crystallography. This allows us to see how the protein functions on a molecular level, along with the details of its interactions with binding partners. Thus far we have produced crystals of fVIII in complex with IgG antibodies 3E6 FAB and G99 FAB, along with the TIL’E’ domain of binding partner von Willebrand factor. These crystals have exhibited limited diffraction, and we are working towards optimizing crystals to increase the resolution of the diffraction pattern. The structure of hybrid fVIII has not yet been studied in detail, and this information could demonstrate its viability, bringing us one step closer to a long-term, effective, and economical treatment of hemophilia.

Rights

Copying of this document in whole or in part is allowable only for scholarly purposes. It is understood, however, that any copying or publication of this documentation for commercial purposes, or for financial gain, shall not be allowed without the author's written permission.

Language

English

Format

application/pdf

Included in

Chemistry Commons

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May 19th, 12:00 PM May 19th, 3:00 PM

Solving the molecular structure of hybrid human-porcine factor VIII through X-ray crystallization

Chemistry

Factor VIII (fVIII) is a protein that is involved in the coagulation cascade, a collection of reactions that is activated by injury and leads to the formation of blood clots. Deficiencies in fVIII lead to the bleeding disorder hemophilia A, a condition that occurs in 1 in 5000 births. The current treatment for hemophilia A is inefficient and costly; however, there is potential through the use of recombinant hybrid human-porcine fVIII. Hybrid fVIII shows up to 12-fold higher coagulant activity than human fVIII, and can retain its activity even in the presence of inhibitory antibodies. The primary objective of our study is to determine the molecular structure of full-length hybrid human-porcine fVIII through X- ray crystallography. This allows us to see how the protein functions on a molecular level, along with the details of its interactions with binding partners. Thus far we have produced crystals of fVIII in complex with IgG antibodies 3E6 FAB and G99 FAB, along with the TIL’E’ domain of binding partner von Willebrand factor. These crystals have exhibited limited diffraction, and we are working towards optimizing crystals to increase the resolution of the diffraction pattern. The structure of hybrid fVIII has not yet been studied in detail, and this information could demonstrate its viability, bringing us one step closer to a long-term, effective, and economical treatment of hemophilia.

 

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