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SUMMARY:Analysis and Design of Proton Transporters
DTSTART:20160329T121500
DTSTAMP:20260428T060824Z
UID:942bc1206f2e4ceafa4cb0b91bc1fbf758ca8b587673962d9d1ca2c3
CATEGORIES:Conferences - Seminars
DESCRIPTION:Prof. William F. DeGrado\, University of California\, San Fran
 cisco\, CA (USA)\nDISTINGUISHED LECTURE IN BIOLOGICAL ENGINEERING(sandwich
 es served)Abstract:\nThe mechanisms by which membrane proteins conduct pro
 tons and use proton gradients to drive the transport of other molecules an
 d ions up their concentrations are important problems in structural biolog
 y.  This talk will focus on a designed transporter\, Rocker\, and a natur
 al proton transporter\, M2.  The M2 proton channel from influenza A virus
  is required for the acidification of the interior of endosomally entrappe
 d virus during the life cycle of the virus.  To investigate the mechanism
  by which protons are transported through the channel we previously determ
 ined crystal structures of the channel using crystals that diffract to 1.0
 5 Å resolution using conventional synchrotron radiation at low and high p
 H\, and at cryogenic as well as room temperature.  At cryogenic temperatu
 res we observe strings of water molecules that appear well oriented to tra
 nsmit protons to a cluster of histidine residues deep within the pore. How
 ever\, the water was far less ordered in crystal structures determined at 
 room temperature\, leaving two possibilities: 1) the lack of order might b
 e associated with radiation damage\; or 2) the water wires seen at low tem
 perature might be an artifact of low temperatures.  Most recently\, we ar
 e using the X-ray free electron laser (XFELs) to investigate the room temp
 erature structures.  Although work is still in progress\, our preliminary
  results indicate that ordered water wires are present in the r.t. structu
 res solved using XFELs crystallography\, although the geometry differs fro
 m that seen at room temperature.  Thus\, the lack of order seen using con
 ventional synchrotron radiation was due to radiation damage.  We also are
  using these structures to assess the relative merits of different water m
 odels used in molecular mechanics force fields.  M2 is also the target of
  the amantadine class of drugs\, but the emergence of drug-resistant virus
 es has become a major problem that curtailed the use of this class of ther
 apeutics.  We have solved the structure of the drug-resistant mutants\, a
 nd used this information to design new drugs that inhibit the most problem
 atic mutant forms of the channel.\nThe second portion of the talk will foc
 us on the de novo design of a transporter\, which uses a proton gradient t
 o drive the transport of Zn(II) and vice verse.  The protein was designed
  to test concepts previously suggested by other investigators to be import
 ant for the evolution of this class of proteins.  These mechanisms featur
 e gene duplication of a primordial unit and “frustrated symmetry” of t
 he otherwise symmetrical protein to cause it to rock between states in whi
 ch the substrates can alternately access the pore from either side of the 
 membrane (but not both sides simultaneously).  Using computational design
  algorithms to stabilize the desired asymmetric states relative to the ful
 ly symmetrical state\, we designed a membrane-spanning four-helical bundle
  that transports transition metal ions Zn(II) and Co(II) – but not Ca(II
 ) – across a membrane. The conduction path was designed to contain two d
 i-metal binding sites\, which display negative cooperativity in their bind
 ing characteristics.  X-ray crystallography\, solids NMR\, solution NMR a
 nd molecular dynamics calculations indicate that the overall helical bundl
 e is formed from two tightly interacting pairs of helices\, which form ind
 ividual domains that interact weakly along a more dynamic interface to all
 ow conduction of ions between the binding sites.  Vesicle flux experiment
 s show that as Zn(II) ions diffuse down their concentration gradients into
  the vesicles\, protons diffuse outward\, even in the presence of an unfav
 orable pH gradient.  Current work is focused on improving overall antipor
 t efficiency.Bio:\nEducation:\nPhD\, Chemistry\, University of Chicago\, 1
 981\nBS\, Chemistry\, Kalamazoo College\, 1977\nPositions:\n1977-1996   
 DuPont Central Research & Development\n1996-2011   Professor\, Universit
 y of Pennsylvania\, Philadelphia\, PA\nsince 2011  Professor\, Dept. of P
 harmaceutical Chemistry\, and Investigator\, Cardiovascular Research Insti
 tute\, UCSF\, San Francisco
LOCATION:SV1717.1 http://map.epfl.ch/?room=sv1717.1
STATUS:CONFIRMED
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