Download Week 16

Tools and Algorithms in Bioinformatics
GCBA815, Fall 2015
Week-16: Structural Bioinformatics
Babu Guda
Department of Genetics, Cell Biology and Anatomy
University of Nebraska Medical Center
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Structural Bioinformatics
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Structural View of Biology
•  The function of a biological macromolecule is highly dependent on its
structural confirmation
•  Deciphering the structure of DNA (double-helix) has revolutionized
molecular biology research
•  Similarly, understanding the structure of proteins/enzymes help
researchers to identify suitable drug targets and design appropriate
drugs
•  While a lot of proteins act as enzymes, there are a number of structural
proteins that support cellular and tissue-level infrastructure and aid in
intra and inter cellular communication
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Binding of a drug compound to a cancer-related protein, MDM2
Human cancer-related protein (MDM2) with embedded small-molecule
drug compounds (“nutlin”). MDM2 is shown as stick figures; “nutlin” is
shown as small cyan colored spheres (van der Wall’s radii).
Picture taken from BayeNetwork
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Nutlin-MDM2 binding activates P53
•  Nutlins are cis-imidazoline analogs that can inhibit the
interaction between MDM2 and tumor suppressor P53, a
tumor suppressor gene
•  It stabilizes P53, which induces senescence (growthinhibition) in cancer cells.
•  Nutlin family of small molecules are widely used in anticancer studies
•  The structure of MDM2 bound to Nutlin was solved
(4HG7) to understand how Nutlin binds to MDM2.
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Structural protein examples
•  Actin: Support the size, shape, structure and motion of cells
•  Cadherin: Adhesive proteins that glue cells together
•  Clathrin: Vesicular trafficking
•  Collagen: About 25% of all protein in our body
•  Integrins: On the cell surface, linking cells
•  Vaults: Symmetrical shells made of vault proteins
•  PDB-101:
•  http://pdb101.rcsb.org/
•  http://mm.rcsb.org/
•  http://pdb101.rcsb.org/learn/resources/videos
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The 20 natural amino acids
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Structural Forms of Proteins
Primary structure: The linear amino acid sequence of the polypeptide (PP) chain
including post-translational modifications and disulfide bonds.
n  Secondary structure: Local structure of linear segments of the PP backbone atoms
without regard to the conformation of the side chains.
n  Tertiary structure: The three-dimensional arrangement of all atoms in a single PP
chain.
n  Quaternary structure: The arrangement of separate PP chains (subunits) into the
functional protein
n 
Bovine Mitochondrial F1-Atpase (ATP
Calcium/Calmodulin-Dependent
Synthase Chain Heart Isoform; Ec:
Protein Kinase
3.6.1.34) Chain α : A, B, C; Chain β: D, E,
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F; Chain γ: G
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Protein Data Bank (PDB)
http://www.rcsb.org/pdb
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Rodes, 2006
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Protein structure data format: PDB
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PDB IDs
•  Four letter code for the compound, case insensitive (Ex: 2HHB)
•  Always start with a numeric followed by alphanumeric
•  Each compound may have multiple chains, a chain ID is denoted
by compound ID followed by ‘:’ and chain identifier (Ex: 2HHB:A)
•  If the compound has only one chain (monomer), ‘_’ denotes the
chain position (Ex: 1BBS:_)
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Structure Alignments
•  Structural alignment involves
establishing equivalencies between
residues in two or more proteins
based on their 3D-coordinates
•  3-D coordinates from C-α atoms are
most commonly used for calculation
of distance in structural alignments
L
L
F
I
R
K
R
K
F
F
G
R
L
W
G
P
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Protein 3-D Visualization Tools
•  Jmol (http://jmol.sourceforge.net)
•  Simple viewer (PDB)
•  Protein workshop (PDB)
•  QuickPDB viewer (PDB)
•  DeepView - Swiss-Pdb Viewer (http://spdbv.vital-it.ch/)
•  PyMOL (http://ww.pymol.org)
•  KiNG viewer (http://http://kinemage.biochem.duke.edu/software/king.php)
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Visualization of Protein Structures
•  All Alpha:
•  Haemoglobin – 1BAB
•  K+ Channel Protein - 1BL8
•  All Beta : Porin - 2POR
•  Mixed Alpha-beta: TIM barrel -1YPI
Beautiful Protein Structures
•  Hemolysin (7AHL)
•  Ribonuclease inhibitor (2BNH)
•  Hydroperoxide resistance protein (1VLA)
7AHL
2BNH
1VLA
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