Part I : Introduction to Protein Structure

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Part I Introduction to Protein Structure

• A/P Shoba Ranganathan
• Kong Lesheng
• National University of Singapore

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Overview

• Why protein structure?
• The basics of protein
• Levels of protein structure
• Structural classification of protein structure

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Why protein structure?

• In the factory of living cells, proteins are the
  workers, performing a variety of biological
  tasks.
• Each protein has a particular 3-D structure that
  determines its function.
• Structure implies function.
• Structure is more conserved than sequence.
• Protein structure is central for understanding
  protein functions.

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To understand functions, we need structures
a- conotoxin ImI and its three mutants
Rogers et al., 2000, JMB 304, 911
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Anfinsens thermodynamic hypothesis

• The three-dimensional structure of a native
  protein
• in its normal physiological milieu (solvent, pH,
  ionic
• strength, presence of other components such as
• metal ions or prosthetic groups, temperature,
  etc.)
• is the one in which the Gibbs free energy of the
• whole system is lowest that is, that the native
  
• conformation is determined by the totality of
• interatomic interactions and hence by the amino
• acid sequence, in a given environment.

--- Anfinsens Nobel lecture, 1972
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What drives protein folding?

• Hydrophobic effects
• Hydrophobic residues tend to be buried inside
• Hydrophilic residues tend to be exposed to
  solvent
• Hydrogen bonds help to stabilize the structure.

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Overview

• Why protein structure?
• The basics of protein
• Levels of protein structure
• Structural classification of protein structure

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The basics of protein

• Proteins have one or more polypeptide chains
• Building blocks 20 amino acids.
• Length range from 10 to 1000 residues.
• Proteins fold into 3-D shape to perform
  biological functions.

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Common structure of Amino Acid
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Aliphatic residues
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Aromatic residues
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Charged residues
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Polar residues
S
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The odd couple
Cb
Cg
Side chain H
Cd
Ca
Ca
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The peptide bonds
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Coplanar atoms
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Backbone torsion angles
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Ramachandran / phi-psi plot
b-sheet
a-helix (left handed)
y
a-helix (right handed)
f
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Overview

• Why protein structure?
• The basics of protein
• Levels of protein structure
• Structural classification of protein structure

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Primary structure

• The amino acid sequences of polypeptides chains.

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Secondary structure

• Local organization of protein backbone ?-helix,
  ?-strand (which assemble into ?-sheet), turn and
  interconnecting loop.

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Ramachandran / phi-psi plot
b-sheet
a-helix (left handed)
y
a-helix (right handed)
f
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The ?-helix

• First structure to be predicted (Pauling, Corey,
  Branson, 1951) and experimentally solved (Kendrew
  et al., 1958) myoglobin
• One of the most closely packed arrangement of
  residues.
• 3.6 residues per turn
• 5.4 Å per turn

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The ?-sheet

• Backbone almost fully extended, loosely packed
  arrangement of residues.

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Topologies of ?-sheets
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Tertiary structure

• Packing the secondary structure elements into a
  compact spatial unit.
• Fold or domain this is the level to which
  structure prediction is currently possible.

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Quaternary structure

• Assembly of homo or heteromeric protein chains.
• Usually the functional unit of a protein,
  especially for enzymes

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Structure comparison facts

• Proteins adopt only a limited number of folds.
• Homologous sequences show very similar
  structures variations are mainly in
  non-conserved regions.
• There are striking regularities in the way in
  which secondary structures are assembled (Levitt
  Chothia, 1976).

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Overview

• Why protein structure?
• The basics of protein
• Levels of protein structure
• Structural classification of protein structure

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• There are two major databases for protein
  structural classification SCOP and CATH.
• They have different classification hierarchy and
  domain definitions.

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SCOP

• http//scop.mrc-lmb.cam.ac.uk/scop/
• Structural Classification Of Proteins database
• Classification is done manually
• All nodes are annotated

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SCOP at the top of the hierarchy
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The hierarchy in SCOP
5 classes All-?, All-ß, ?/ ß, ? ß, multi-domain
Have the same major secondary structure
topological connections
Probable common ancestry
Clear evolutionary relationship
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CATH

• http//www.biochem.ucl.ac.uk/bsm/cath
• Class-Architecture-Topology-Homologous
  superfamily
• Manual classification at Architecture level but
  automated at Topology level

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The hierarchy in CATH
3 classes Mainly-?, Mainly-ß, ?-ß
Overall shape as determined by orientations of
secondary structures

Both the overall shape connectivity of
secondary structure
Share a common ancestor
Classified based on sequence identity