A cell is an organization of millions of molecules
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A cell is an organization of millions of moleculesA cell is an organization of millions of molecules
Proper communication between these molecules Proper communication between these molecules is essential to the normal functioning of the cell is essential to the normal functioning of the cell
To understand communication between To understand communication between molecules:molecules: *determine the arrangement of the atoms*
Organ Organ Tissue Tissue Cell Cell Molecule Molecule Atoms Atoms
Structural BiologyStructural BiologyMedicine and Biology at the Atomic ScaleMedicine and Biology at the Atomic Scale
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High Resolution Structural BiologyHigh Resolution Structural Biology
Using atomic structure to understand how Using atomic structure to understand how biomolecules communicatebiomolecules communicate
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Anti-tumor ActivityDuocarmycin SA
The Reward: UnderstandingThe Reward: UnderstandingControlControl
Shape
Atomic interactions
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Hierarchy of Structural BiologyHierarchy of Structural Biology
MoleculeStructural Genomics
PathwayStructural Proteomics
ActivitySystems Biology
RPARPANER
BER
RR
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High Resolution Structural BiologyHigh Resolution Structural BiologyThree Complementary TechniquesThree Complementary Techniques
NMR Spectroscopy X-ray Crystallography
Computation
Determine experimentally or modelDetermine experimentally or model3D structures of biomolecules3D structures of biomolecules
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What Tools Do We Use?What Tools Do We Use?
NMRNMR ComputationComputation
RPA-B
RPA-AB
RPA-A
Fluo
resc
ence
Inte
nsity
Ratio of T-ag/RPA
Biophysical AnalysisBiophysical AnalysisExpression/MutationsExpression/Mutations CrystallographyCrystallography
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Experimental DeterminationExperimental Determination of 3D Structures of 3D Structures
X-ray
X-raysDiffraction
Pattern
Direct detection ofatom positions
Crystals
NMR
RFRF
Signals
H0
Indirect detection ofH-H distances
In solution
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Representations of StructureRepresentations of Structure Conformational EnsembleConformational Ensemble
PRECISIONRMSD of the ensemble
Neither crystal nor solution structures are properly represented by a single conformation Intrinsic motions Imperfect data
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Computational Determination Computational Determination of 3D Structuresof 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 Unique Contributions of Each Structural Biology TechniqueStructural 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 Challenges For Understanding The Meaning of StructureThe 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 StructuresVisualization of Structures
Intestinal Ca2+-binding protein!
Need to incorporate 3D and motion
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Calcium-Dependent Protein KinaseCalcium-Dependent Protein KinaseA Target for Anti-Malarial Drug DesignA Target for Anti-Malarial Drug Design
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Ca2+
Target(kinase)
Calcium Signal TransductionCalcium Signal Transduction
EF-Hand Ca2+ Sensors
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Regulation of Protein Kinase Regulation of Protein Kinase Activity by CaActivity by Ca2+2+-Calmodulin -Calmodulin
CaCa2+2+ signal signal
Kinase ActivationKinase Activation
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Protozoa Have A Unique Kinase Protozoa Have A Unique Kinase The CaThe Ca2+2+-Dependent Protein Kinase (CDPK)-Dependent Protein Kinase (CDPK)
Kinase
CDPK has its own regulatory apparatus!!How does it work?
Standard auto-inhibitory segment
Calmodulin-like domain (CaM-LD)
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Structure of CDPK RevealsStructure of CDPK RevealsIntra-molecular Kinase ActivationIntra-molecular Kinase Activation
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Anti-Malarial Drug DesignAnti-Malarial Drug DesignMust Inhibit CaM-LD But Not CalmodulinMust Inhibit CaM-LD But Not Calmodulin
Calmodulin CaM-LD
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Center for Structural BiologyCenter for Structural BiologyA Trans-Institutional InitiativeA 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 ResourceStructural Biology ResourceBut Not A Core!!But 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