Center for Structural Biology

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Structural Biology Medicine and Biology at the
Atomic Scale
Organ ? Tissue ? Cell ? Molecule ? Atoms

• A cell is an organization of millions of
  molecules
• Proper communication between these molecules is
  essential to the normal functioning of the cell
• To understand communication between molecules
  determine the arrangement of the atoms

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High Resolution Structural Biology

• Using atomic structure to understand how
  biomolecules communicate

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The Reward Understanding?Control
Atomic interactions
Shape
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Hierarchy of Structural Biology
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High Resolution Structural BiologyThree
Complementary Techniques

• NMR Spectroscopy X-ray
  Crystallography
• Computation

Determine experimentally or model 3D structures
of biomolecules
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What Tools Do We Use?
Crystallography
Expression/Mutations
NMR
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Experimental Determination of 3D Structures
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Representations of Structure Conformational
Ensemble

• Neither crystal nor solution structures are
  properly represented by a single conformation
• Intrinsic motions
• Imperfect data

PRECISION RMSD of the ensemble
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Computational Determination of 3D Structures

• Specify the forces that act on each atom
• Simulate these forces on a molecule of known
  atomic composition
• Start with experimental data or approximate
  experimental structure or just sequence
• Many algorithms in use, all treatments for
  bio-macromolecules are empirical

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Unique Contributions of Each Structural Biology
Technique

• X-ray- highest resolution, automation coming
• NMR- enables wide variation of solution
  conditions direct characterization of motions
  and of weakly interacting systems
• Computation- fundamental understanding of
  structure, dynamics and interactions models
  without experiment fast

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Challenges For Understanding The Meaning of
Structure

• Structures determined by NMR, computation, and
  X-ray crystallography are static snapshots of
  highly dynamic molecular systems

• Biological process (recognition, interaction,
  chemistry) require molecular motions (from
  femto-seconds to minutes)
• New methods are needed to comprehend and
  facilitate thinking about the dynamic structure
  of molecules visualization

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Visualization of Structures
Intestinal Ca2-binding protein!

• Need to incorporate 3D and motion

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Calcium-Dependent Protein KinaseA Target for
Anti-Malarial Drug Design
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Calcium Signal Transduction
EF-Hand Ca2 Sensors
Ca2
Target (kinase)
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Regulation of Protein Kinase Activity by
Ca2-Calmodulin
Ca2 signal
Kinase Activation
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Protozoa Have A Unique Kinase The Ca2-Dependent
Protein Kinase (CDPK)
Standard auto- inhibitory segment
Calmodulin-like domain (CaM-LD)

• CDPK has its own regulatory apparatus!!
• How does it work?

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Structure of CDPK RevealsIntra-molecular Kinase
Activation
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Anti-Malarial Drug DesignMust Inhibit CaM-LD But
Not Calmodulin
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Center for Structural BiologyA
Trans-Institutional Initiative

• Increase molecular/physical thinking in medical
  and biological research
• Foster multi-disciplinary approaches
• Focal point bridging medicine and biology to
  physics and chemistry

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Structural Biology ResourceBut Not A Core!!

• Education/project origination
• Enabling expertise 3 Ph.D. Staff Scientists
• Enabling hardware technologies to visualize and
  determine structures
• Open-access focal point in BIOSCI/MRBIII