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Tutorials for protein data bank and swiss PDB viewer
2010/04/19Prof. Jinn-Moon Yang
Yen-Fu Chen and Kai-Cheng Hsuhttp://gemdock.life.nctu.edu.tw/dock/download/20100419_spv.ppthttp://gemdock.life.nctu.edu.tw/dock/download/20100419_spv.pdf
http://ppt.cc/cnqT (ppt)http://ppt.cc/WWxd (pdf)
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Contents
Introduction of protein structuresUsing thymidine kinase as an example
Download and installTutorial
Download protein structures from PDBBasic Operation Advance Operation
Resources for tutorialhttp://www.youtube.com/watch?v=yFE3CAHNkZg&feature=related
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Introduction of protein structures
Proteins present in all biological organismsPolymers of amino acids (20 L-α-amino acids)NanoparticlesPerform particular biochemical functions
Nature: Mattson, M. Nature. 422, 385-387 (2003)stemcells.nih.go: Early Development
Transcription and translation Cell regulation and catalysis reactions
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Introduction of protein structures
To enable to perform protein’s biological function, protein fold into one or more specific spatial conformations driven by noncovalent interactions
Hydrogen bonding, ionic interactions, van der Waals forces and hydrophobic packing
3D protein structures are necessary for understanding the functions of protein at molecular level
Adapted from Protein Structure in Wikipedia
Hemoglobin: oxy-deoxy states
Adapted from structural biology Wikipedia
Protein structure: from amino acid to quaternary structure
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Noncovalent interactions for protein structure and function
Ionic bondA bond formed by the attraction between two oppositely charged ions
Hydrogen bondAn attractive interaction of a hydrogen atom with an electronegative atom, like N,O, and F
Na Cl
Na Cl
Potential energy of Na and Cl Potential energy of Na and Cl
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Noncovalent interactions for protein structure and function
van der Waals forceAttractive or repulsive force between molecules
Hydrophobic interactionThe physical property of a molecule (known as a hydrophobe) that is repelled from a mass of water
An example of van der Waals force:Gecko climbs on the glass
An example of hydrophobic interaction:Water drops on hydrophobic surface
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Protein structure database:Protein data bank (PDB)
Techniques for determining atomic structuresX-ray crystallography, NMR spectroscopy and electron microscopy
PDB contains information about experimentally-determined structures of biological marcomoleculeas (proteins, and DNA/RNA)
Proteins (1kim)
DNAs/RNAs (2k7e)
Biological complexes (1zrc)
X-ray
NMR
EM
http://www.pdb.org/
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Search protein structures in PDB
PDB provides search by protein name, ligand, or structrue related keywords
Search example: thymidine kinase (TK)
• Function: DNA synthesis
• Therapeutic: Anticancer and antivirus drug target
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Example: X-ray structures of virus’ thymidine kinase with substrates/inhibitors
Protein name
Source spices
Experimental method
has ligands
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Search result of “X-ray structures of virus’ thymidine kinase with substrates/inhibitors”
TK of virus
TK with ligand (substrate)
PDB ID of this structure
X-ray structure
23 structures for these keywords
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Structure and related data (1kim)
The citation of this structure
Related data of this structure
The title of this structure
Visualization of biological assembly
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Structure and ligand data (1kim)
Ligand in this structure
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Structure and sequence data (1kim)Related data of this structure
Sequence ID of 1kim in UniProtKB
Structure classification ID of 1kim
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Advance inspection for protein structure: download structure from PDB
1. Save the data on your PC2. Open the file on a structure
viewer program (swiss PDBviewer, pymol, and etc.)
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Classification of Drug Development
Protein (receptor) Structure
Compound structure Known Unknown
Known
Unknow
n
Structure-based Drug Design (SBDD)
SBDD or de novo design
High-Throughput Screening(HTS)
Compound similarity searchO
O
O
O
O
O
query Similar compounds
O O
DDT 2002
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Discovering new leads
Curr. opin. Chem. Biol. 2002, 439
Yellow: virtual screening (SBDD)Blue: high-throughput screening (HTS)
HTSSBDD
• There are more than 5 H-bond donors.• The molecular weight is over 500.• The LogP is over 5.• There are more than 10 H-bond acceptors.
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Drugs derived from structure-based approaches
Drug Discovery Today, 10, 895, 2005
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Drug Discovery Today, 10, 895, 2005
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Tutorial for Swiss PDB viewer
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Download and installDownload Swiss PdbViewer
http://spdbv.vital-it.ch/download.html
Download user guidehttp://spdbv.vital-it.ch/Swiss-PdbViewerManualv3.7.pdf
Tutorial video (English)http://www.youtube.com/watch?v=nYT5qwtfNew&feature=relatedhttp://www.youtube.com/watch?v=yFE3CAHNkZg
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General Terms
Gray: C atomBlue: N atomRed: O atom
Residue Arginine
Side chain
Main chain
Atom radius
ChainSecondary
Structure (Ribbon)
A protein may have multiple chains
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Install and execute swiss pdb viewer
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Workspace
Control panel
Layer info
Main window
Viewer
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Move & Rotate Center Zoom
Translate Rotate
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Open control panel
control panel
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Display or hide residues-for some residues
Press left button of mouse
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Display or hide residues-for all residues
Press right button of mouse
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Display or hide side chains of residues
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Display or hide residue labels
GLU111
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Display or hide atom radius
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Render in solid 3D
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Show secondary structures -Display or hide ribbons
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Bond length
1.52A
1 angstrom (A) or 1 × 10−10 meters ?A
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Hydrogen bond length
?A
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Hydrogen bonds of helix
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Hydrogen bond of helix
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Hydrogen bonds of helix
Helix
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Hydrogen bonds of sheet
SheetResidue 50~55
201~207323~328
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Number of helix ?From residue 46~146
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Visualization of biological assembly-color by chain
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Change color by chain-act on Ribbons
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Show residue properties-Change color by Type
Type Reisdue Negative ASP
GLUPositive HIS
LYSARG
Polar SERTYRASNTHRGLN
Hydrophobic CYS
METPHEALATRPLEUILEPROVAL GLY
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Show structure flexibility Change color by B-factor
A low B-factor meaning that the position of the atom has been determined with accuracy
High B-factor
Low B-factor
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Other color types
Secondary Structure
Selected residues
Relative accessibility
default atom colors
Root mean square between 2 molecules
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Thymidine kinase
• Function: DNA synthesis
• Therapeutic: Anticancer and antivirus drug target
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Analyze protein-ligand interactions-Select ligands (or residues)
Press left button of mouseto select the ligand (THM, thymidine) of 1kim
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Identify binding site-Show protein (ribbon) and ligand (stick)
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Select residues in the binding site-Neighbors of selected residues
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Center selected residues
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H-bonds of the binding site-Compute H-bonds
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H-bonds between protein and ligand-Show H-bonds of selection
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H-bonds between TK and THM-Show residues from selection
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Show residue labelPress right button of mouse
1. Q125 recognize the thymine moiety2. Activity was decreased by over
90% if Q125 mutated (Biochemistry, 2000. 39: p. 4105-4111)
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van der Waal forces-Stacking interactions
M128 and Y172 sandwich the thymine moiety Stabilize the binding of substrate (JBC, 1999. 274: p. 31967-31973)
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Observe the protein surface -Compute Surface
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Surface preference
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Show ligand in the surface
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Comparison of multiple structures-Import PDB
PDB code: 3vtkAnother structure of thymidine kinase
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Open layer info
1kim
3vtk
Show or hide
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Superimpose two molecules
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Results of superimposition
RMS: 0.63 ǺMeasure the structure similarity
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Comparison of binding sites-Neighbors of selected residues
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Comparison of ligands
HO O
HON O
NHO
HO
OOPO
HO
HO
N
I
ONH
O
1kim: substrate(CPK)3vtk: inhibitor (Green)
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Homework
Keyword1. Capture a picture of N1 neuraminidase (ribbon) and its ligand (stick)2. Capture a picture of H-bonds between protein and ligand
[email protected] title: 學號姓名 _HW2