NMR spectroscopy in post-genomic era

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Introduction

• NMR spectroscopy in post-genomic era
• AC 7121 Spring 2004

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Nobel for Magnetic Resonance

• Isador I. Rabi
• Nobel Prize in Physics, 1944
• For his resonance method for recording the
  magnetic properties of atomic nuclei.

• Felix Bloch and Edward M. Purcell, USA
• Nobel Prize in Physics, 1952
• The NMR phenomenon was demonstrated for protons
  in 1946.

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Nobel for Magnetic Resonance

• Richard Ernst, Zurich,
• Nobel Prize in Chemistry, 1991
• For his fundamental contributions to NMR
  methodology-Nuclear Magnetic Resonance Fourier
  Transform Spectroscopy
• http//www.nobel.se/chemistry/laureates/1991/erns
  t-lecture.html
• Kurt Wüthrich
• Nobel Prize in Chemistry, 2002
• NMR studies of structure and function of
  biological macromolecules.
• . http//www.nobel.se/chemistry/laureates/2002/wu
  thrich-lecture.html

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Nobel for Magnetic Resonance

• Paul C. Lauterbur (Urbana, IL) and Sir Peter
  Mansfield (Nottingham, UK)
• Nobel Prize in Physiology or Medicine, 2003
• For their pioneering contributions which led to
  the application of magnetic resonance in medical
  imaging.

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Nobel for Magnetic Resonance

• Alexeij A. Abrikosow (Argonne, IL) and Vitalij L.
  Ginzburg (Moscow)
• Nobel Prize in Physics, 2003
• For pioneering contributions to the theory of
  type-II superconductors, i.e., those alloys
  capable of withstanding the high magnetic fields
  that occur in MR applications.

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From Sequence to function Example 1 Ompx from
E.Coli
tctagacttaagtaaagcgtggagtgtactggatatacccaatgctggtt
gagcatttgttgaaaaaattttcccccgttttgactaaaatgcgccagga
ttgatggaatcattagtctggtgattaggaataatctggatgaatgacag
ggaaaacatgcgtaatacttacgcagttctctgaaaaagtgatttaaatt
tagatggatagcggtgtatggaaacgttctgttacatgaaatggcccgtt
agacatcacaaatcgcgaagagtttcccattaatttttgatatatttaaa
acttaggacttatttgaatcacatttgaggtggttatgaaaaaaattgca
tgtctttcagcactggccgcagttctggctttcaccgcaggtacttccgt
agctgcgacttctactgtaactggcggttacgcacagagcgacgctcagg
gccaaatgaacaaaatgggcggtttcaacctgaaataccgctatgaagaa
gacaacagcccgctgggtgtgatcggttctttcacttacaccgagaaaag
ccgtactgcaagctctggtgactacaacaaaaaccagtactacggcatca
ctgctggtccggcttaccgcattaacgactgggcaagcatctacggtgta
gtgggtgtgggttatggtaaattccagaccactgaatacccgacctacaa
acacgacaccagcgactacggtttctcctacggtgcgggtctgcagttca
acccgatggaaaacgttgctctggacttctcttacgagcagagccgtatt
cgtagcgttgacgtaggcacctggattgccggtgttggttaccgcttcta
atcactttggtgatataaaaaatccgcctctcggggcggatttttgtttt
taaggtttcgggtcgaaaatatc
ATSTVTGGYAQSDAQGQMNKMGGFNLKYRYEEDNSPLGVIGSFTYTEKSR
TASSGDYNKNQYYGITAGPAYRINDWASIYGVVGVGYGKFQTTEYPTYKN
DTSDYGFSYGAGLQFNPMENVALDFSYEQSRIRSVDVGTWIAGVGYRF
Outer Membrane Protein Ompx from Escherichia Coli
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From Sequence to function Example 2 GLUTAMINE
SYNTHETASE from Salmonella typhimurium
MSAEHVLTMLNEHEVKFVDLRFTDTKGKEQHVTIPAHQVNAEFFEEGKMF
DGSSIGGWKGINESDMVLMPDASTAVIDPFFADSTLIIRCDILEPGTLQG
YDRDPRSIAKRAEDYLRATGIADTVLFGPEPEFFLFDDIRFGASISGSHV
AIDDIEGAWNSSTKYEGGNKGHRPGVKGGYFPVPPVDSAQDIRSEMCLVM
EQMGLVVEAHHHEVATAGQNEVATRFNTMTKKADEIQIYKYVVHNVAHRF
GKTATFMPKPMFGDNGSGMHCHMSLAKNGTNLFSGDKYAGLSEQALYYIG
GVIKHAKAINALANPTTNSYKRLVPGYEAPVMLAYSARNRSASIRIPVVA
SPKARRIEVRFPDPAANPYLCFAALLMAGLDGIKNKIHPGEPMDKNLYDL
PPEEAKEIPQVAGSLEEALNALDLDREFLKAGGVFTDEAIDAYIALRREE
DDRVRMTPHPVEFELYYSV
GLUTAMINE SYNTHETASE
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From Sequence to function Example 3 Antennapedia
homeodomain
The polypeptide chain in this protein is
partially folded, with both ends showing
pronounced disorder.
In complex with its operator DNA, the N-terminal
chain end is located in the minor groove of the
DNA, where the polypeptide adopts a well-defined
structure.
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From Sequence to function Example 4 Amyloid
peptide
Structure Of Transthyretin In Amyloid Fibrils
Determined By Solid-State Magic Angle Spinning NMR
Solution Structure Of The Alzheimer'S Disease
Amyloidb-Peptide (1-42)
1IYT
1RVS
Two Types of Alzheimers b-Amyloid (140) Peptide
Membrane Interactions Aggregation Preventing
ransmembrane Anchoring Versus Accelerated Surface
Fibril Formation
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From Sequence to function Example 4 Amyloid
peptide
Solution Structure Model of Residues 1-28 of the
Amyloid -Peptide When Bound to MicellesJ. Am.
Chem. Soc. 1998 120(43) pp 11082 - 11091
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From Sequence to function Example 5 Hemoglobin
This view shows haemoglobin cycling between the
oxygen bound and the oxygen free states. As it
does so, the molecule opens up or closes, to
allow O2 (the two red spheres) to float away or
bind to the haem moeity (shown in space filling
model). N.B. Haemoglobin naturally aggregates as
groups of four molecules, 2 alpha and 2 beta
chains. They are shown in monochrome here, but
the four-fold aggregation is the reason for four
oxygen molecules appearing in the animation.
http//www.umass.edu/microbio/chime/hemoglob/2frmc
ont.htm http//www.andrew.cmu.edu/user/jl2p/Hb_htm
l/gallery.html
1HHO and 4HHB
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From Sequence to function Example 5 Hemoglobin
This animated figure illustrates the motion of
the a2b2 dimer (thick coils towards front)
relative to the a1b1 dimer (thin coils towards
rear) in the oxy-to-deoxy transition. Here, the
coordinates of oxy- and deoxy-Hb have been
superimposed at the a1b1 interface so that the
a1b1 dimer remains stationary. The a2b2 dimer
rotates by 15 degrees about an axis passing
through the a subunits.
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From Sequence to function Example 6 Envelope
Glycoprotein of HIV-1
gp41 fusion peptide in aqueous solution. L7F11
adopt a Type-I b turn.
gp41 fusion peptide in 50 TFE.
Schematic drawing of the insertion of gp41-FP
into the SDS micelle and its interaction with the
5- and 12-DXSA probes. A15 to G16 are depicted at
the micelle-water interface, while 12- and 5-DXSA
are near F8/L9 and 14, espectively.
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From Sequence to functionStructural genomics

• Proteins whose primary sequences are encoded in
  the genomes mediate most of the chemical
  reactions occurring in a living organism. Their
  three-dimensional structures can provide hints to
  an understanding of their functions and,
  ultimately, to an understanding of the chemical
  bases of life itself. Therefore, research leading
  to a complete coverage of protein structures
  logically follows the determination of genome
  sequences. Structural genomics is the field of
  science focused on the systematic determination
  of the three-dimensional structure of the
  proteins encoded into genomes.

Ivano Bertini in Acc. Chem. Res.v36, 3, p155 2003
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From Sequence to function
Yee et. al. Acc. Chem. Res.v36, 3, p187 2003
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From Sequence to function
atgggaattg actacgtggt gttttacctc atacccaata
tagtgggcgg cttttatatg 61 tttattatgg cgctgggggc
ggccaagagg ccgagaagcc acgcctatcc cccgtggag
aactacctcg tcgttgtagt tactgtgggc gatgagaggg
taatgccggc tttagcggag accgtggccc agctggagag
gctggggctg aggtacacag tgctctcctc ccgccccctc
cccattaaaa accacatagt agtgccaaaa aagaggacg
gctctaaata ccgcgcaatt ctctggttcg ttaagaatta
cgccagaaac gacatgtggt atatcttcct tgacgacgac
agctacccat tagatacccg atttttacgc gatattgcat
attacggagc caggggatgc gtggctggca acggcgtgtt
agtgccgagg cccggccgct cagccctcgc atacgcctta
gactggatta ggtatttcca cgacttaact cataccgct
tttccctcga ggtgctcaga aggcctatat tcggcatgca
cggggaattg ttaatagtga ggggggatgt gttgaggagc
atctggccgg ctatgggcga caccattacg gaggatttcc
gcttcgccat ggagctctta aagcgcaggt acaagacttt
tcaaacctcc acaagggtct caattaaaag ccccaactcc
ctgagggact tcgtaagaca gagggccagg ggcggcgg
tatatcaga ggccgccaag tataaaaacg cctattactt
aatcctaacg gcctctccca tcgccctctt cctctcaacc
ccggccagct ggctatacgg cttcacaata cccctcttaa
tctccgcagt ctacgcctcg gtgtatatat acggtagctt
aaaggcgaaa aggtatatat tagacgtgtg gctagcctca
tttcttgaat taatgggctt aataatcggc
ccgcgagaa aggcgaagaa cttctacgta atagacaaga ggtag
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From Structure to function
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From Structure to function
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From Structure to function
nature structural biology structural genomics
supplement november 2000 p991
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Potential impacts on drug discovery
nature structural biology structural genomics
supplement november 2000
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Resources on the Web

• Protein Data Bank
• http//www.rcsb.org/pdb/

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Resources on the Web

• BioMagResBank

http//www.bmrb.wisc.edu/