Application of synthetic antibodies to structural biology: Crystal structures of the closed and the open conformation of full-length KcsA
Başlık çevirisi mevcut değil.
- Tez No: 401062
- Danışmanlar: DR. ANTHONY KOSSIAKOFF
- Tez Türü: Doktora
- Konular: Biyokimya, Biochemistry
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2009
- Dil: İngilizce
- Üniversite: University of Chicago
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Belirtilmemiş.
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 210
Özet
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Özet (Çeviri)
Structural genomic efforts around the world have advanced the field of structural biology through automating processes including protein expression, purification, crystallization and structure determination. Yet, some types of proteins and protein families remain recalcitrant to structural studies. In particular, membrane proteins and protein families that readily form polymers (e.g. actin, tubulin) under crystallization conditions pose daunting challenges to crystallography Membrane proteins are fundamental components of cell physiology. One third of the open reading frames within the known genomes represent membrane proteins whose function is extremely diverse and crucial for cell viability. Additionally, they account for more than 50% of therapeutic targets of the current drugs; highlighting their importance to the pharmaceutical industry and their involvement in human diseases. Acquiring insights about how these molecular machines work is of utmost importance and structural biology has been a key contributor in that regard. Antibody fragments have successfully been used to promote crystallization of several membrane proteins where they provided the necessary crystal contacts for lattice formation. Although employment of antibody fragments for membrane protein crystallization proved to be very productive, generation of these binding molecules through hybridoma technology significantly limits its wide application. In this thesis, I describe the development of a new technology that allows facile production of antibody fragments on a laboratory benchtop. The foundation of our technology, which we call chaperone-assisted crystallography (CAC), is a novel 'reduced genetic code' phage display Fab library that was shown to generate high affinity and specificity synthetic Fabs to soluble proteins and a structured RNA molecule. Here, using five different membrane proteins as target molecules, I demonstrate the capability to produce high affinity synthetic Fabs to a diverse set of membrane proteins. Furthermore, Fabs generated against the full-length (FL) KcsA bacterial potassium channel promoted its crystallization and subsequent structure determination, including its isolated C-terminal cytoplasmic domain (CD). The FL KcsA structure represents the first membrane protein-synthetic Fab chaperone complex and provided important new insights into KcsA's gating, ion permeation and inactivation processes.
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