61 / 103
Page 99
Notes:
conferenceseries
.com
Volume 10, Issue 8 (Suppl)
J Proteomics Bioinform, an open access journal
ISSN: 0974-276X
Structural Biology 2017
September 18-20, 2017
9
th
International Conference on
Structural Biology
September 18-20, 2017 Zurich, Switzerland
Beat Vögeli, J Proteomics Bioinform 2017, 10:8(Suppl)
DOI: 10.4172/0974-276X-C1-0100
Functional protein conformation networks probed by NMR nanorulers
Beat Vögeli
University of Colorado at Denver, USA
T
he function of a protein is tightly connected to its conformational network. Often, subtle differences distinguish
interchanging states with distinct properties. Onemajor challenge in structural biology is a sufficiently complete description
of the structural landscape and the exchange dynamics between structural states at atomic resolution. We have replaced the
standard NMR structure determination by an approach that generates multi-state ensembles from a dense network of tight
averaged distance restraints derived from exact measurements of nuclear overhauser enhancements. Here, we present the
identification of conformational networks harbored by two-human cis/trans isomerases cyclophilin A and Pin1 using the
nanorulers provided by eNOEs. We have previously presented an eNOE-based ensemble description of cyclophilin that reveals
the presence of a closed and an open state, the latter of which pre-organizes the catalytic site for catalysis. Based on this finding,
we demonstrate here a ligand-selective change of the binding affinity to the active site by tuning the dynamics of a highly
flexible loop. We show that the binding affinity is increased upon substitution of double glycines to alanines at either of the
hinge regions of a loop. The equilibrium distribution is shifted towards more binding-competent conformations. Comparison
of the eNOE-based ensembles of the free and ligand-bound WW domain of Pin1 reveals a conformational network that
extends into the interface formed with the enzymatically active PPIase domain. This finding may offer an atomic-picture
explanation for the previously discovered communication between the two domains.
Biography
Beat Vögeli has his expertise in nuclear magnetic resonance (NMR) spectroscopy of biomacromolecules. He develops methodology for the elucidation of
conformation and communication networks within and between proteins and nucleic acids. He received his PhD degree at the ETH Zürich in the group of Konstantin
Pervushin. After a postdoctoral stay at the National Institutes of Health, Bethesda USA, in the group of Ad Bax, he returned to ETH Zürich to become Oberassistant
in the group of Roland Riek and Privatdozent. He is currently an Assistant Professor at the University of Colorado at Denver in the Department of Biochemistry
and Molecular Genetics.
beat.vogeli@ucdenver.eduFigure1:
Conformational network of cyclophilin A. a)
Structural two-state eNOE ensemble representation
of the residues affected by the dynamics of the
binding loop shown in the open (blue) and closed
state (magenta). b) Mechanistic representation for
loop opening and closing for the wildtype, G74A/
G75A mutant and the complex.