1. Protein Structure Flashcards
Describe the basic structure of amino acids.
Amino acids consist of a central carbon atom (Cα) linked to four groups:
- Hydrogen (H)
- Amino (H3N+)
- Carboxylic acid (COO-)
- Carying sidechain (R).
The structure around Cα is tetrahedral (109.5º)
All amino acids are chiral, except for which amino acid?
Glycine.
What do you call the two enantiomers of amino acids?
- Levo isomer
- Dextro isomer
All amino acids in proteins are __-stereoisomers.
Why is this important?
Virtually all amino acids in proteins are L-stereomers, resulting in specific protein structures with asymmetric enzyme active sites. Therefore, amino acids respond to drug therapy only if the drug is in the L-conformation.
Note: Antibiotic penicillin and its derivatives mimic the D-conformation of amino acids.
Why is it important to synthesize a drug that is predominant in one enantiomer?
It is important to synthesize a drug which contain predominantly one enantiomer and not the other, to:
- increase its efficiency
- decrease the toxic effects due to the other chiral conformation.
Single-enantiomer products have the following prefixes: dex-, dextro-, lev-, levo-
List three reasons why enantiomeric excess is preferred in drug therapies?
- Only one enantiomer is active and the other is inactive.
- One of the enantiomers is less active.
- One of the enantiomers is toxic.
Why is Ibuprofen packaged as a racemic mixture, even though only one enantiomer is effective?
For Ibuprofen, it is not economically feasible to isolate a single enantiomer from a racemic mixture or to synthesize just the active one, and therefore a racemic mixture is marketed, with an essentially double the recommended dose.
What does a smaller amino acid side chain generally indicate?
- Less hydrophobic
- More hydrophilic
- Increased solubility in water
What is the difference between cystine and cysteine?
Cysteine are amino acids that can form disulfide bonds (covalent bonding) with other cysteine molecules to form cystine.
Cysteine is polar, whereas cystine is non-polar.
Describe the insulin protein.
Insulin protein consists of 2 polypeptide chains stabilized by 3 disulfide bonds between cysteines.
melatonin
- Hormone produced by the pineal gland that regulates the circadian rhythm
- Production affected by light
- Production starts in the evening, peaks at night, and declines in the morning
- Used to treat sleep disorders such as Seasonal Affective Disorder (SAD), jet-lags, late-night workers
- Tryptophan derivative
serotonin
- Neurotransmitter
- Considered the “feel good” molecule
- Tryptophan derivative
- Used to treat major depression, obsessive-compulsive disorder, and other anxiety disorders associated with low serotonin levels in brain.
- Antidepressants (Prozac) increase serotonin levels by inhibiting proteins that reuptake the serotonin.
Name the tryptophan derivatives.
- Serotonin
- Melatonin
Name the tyrosine derivatives.
- DOPA
- Dopamine
- Epinephrine
- Norepinephrine
These neurotransmitters are “fight-or-flight” hormones that are released by the adrenal glands in response to stress.
DOPA
- Tyrosine derivative
- Used to treat some forms of dystonia, a movement disorder that causes the muscles to contract and spasm involuntarily.
dopamine
- Tyrosine derivative
- Dopamine deficiency is associated with depression and attention-deficit hyperactivity disorder.
- High levels has been strongly linked to psychosis and schizophrenia.
norepinephrine
- Tyrosine derivative
- Low levels are associated with depression.
- Small molecules that inhibit reuptake of norepinephrine are used to treat the symptoms.
epinephrine
- Tyrosine derivative
- Used to treat cardiac arrest
- Boosts the supply of oxygen and glucose to the brain and muscles.
creatinine
- Stores high energy phosphate
- Part of ATP is stormed in terms of creatine phosphate
- Excreted by kidneys, the levels in blood is a measure of renal function
What type of bond links amino acids? How does it form?
Draw this bond.
- Amino acids are linked by peptide bonds (residues)
- Peptides bonds are formed by a condensation or dehydration reaction (i.e., removal of water)
What is the protein structure order?
- Primary structure
- Secondary structure
- Tertiary structure
- Quaternary structure
T/F: Peptide bonds in proteins occur in cis configurations?
- Virtually all peptide bonds in proteins occur in trans configuration
- The carbonyl oxygen has a partial negative charge
- The amide nitrogen has a partial positive charge, setting up a simple electric dipole
An exception to this rule are peptide bonds involving the imino nitrogen of proline (6% in the cis configuration).
ß-sheet
- More extended backbone compared to a-helix.
- The backbone is extended into a zigzag rather than helical structure.
- H-bonds between adjacent segments of polypeptide chain (b-strands).
- Parallel or anti-parallel conformations depend on the direction of b-strands.
Describe the parallel conformation of the ß-sheet.
- Aligned main chain atoms, non-linear N-H…O H-bonds
- Repeat unit = 6.5 Å
- Ideal φ = -1190 & ψ = +1130
- Connected via right-handed crossovers
Parallel ß-strands are connected via _____-handed crossovers.
Explain why.
Right.
Right-handed crossovers have a shorter bend through smaller angles.
Note: Arrows indicate the direction from N-terminus to C-terminus.
Describe the antiparallel conformation of ß-sheets.
- Linear N-H…O H-bonds so that all main chain atoms are not aligned
- More stable than parallel conformation
- Repeat unit = 7 Å
- Ideal φ = -1390 & ψ = +1350
Antiparallel ß-strands are connevted via __-turns.
ß.
- ß-hairpin is the main structural motif.
- Stable ß-hairpin consists of two structures:
- ß-turn
- Stabilizing interaction (predominantly hydrophobic, followed by electrostatic) between sidechains of amino acids on b-strands.
What amino acids are often found in ß-turns?
- Gly
- Most flexible sidechain
- Can adopt wide conformations including ß-turn
- Pro
- Has trans and cis forms
- Cis form is always found in ß-turns because the backbone turns back and it is smaller
Describe fibrous proteins in detail.
- Left-handed helix (not an a-helix)
- 3 amino acids per turn
- ~1000 amino acids per chain
- Right-handed supertwist of three chains
- Offer strength and flexibility to the structures in which they occur.
- Fundamental structural unit is a simple repeating element of secondary structure.
- Insoluble in water, because they contain high number of hydrophobic residues.
- Two or more polypeptide chains are packed together to form supramolecular complexes.
- Collagen: Found in tendons, cartilage, organic matrix of bone, and the cornea of the eye
How are fibrous proteins structurally modified in collagen molecules to provide strength?
- Crosslinked for strength by covalent bonds involving Lys, HyLys (5-hydroxylysine), or sometimes histidine
- Specific alignment and degree of cross-linking produce characteristic cross-striations
- Ultimately ~ 3,000 Å long and 15 Å thick
- Considered stronger than steel
Describe how complex motifs can be built up from simple secondary structures.
- Joining a series of simple β-α-β motifs to create a a/b barrel motif.
- In this structure, each parallel β segment is attached to its neighbor by an α-helical segment.
- All connections are right-handed.
hemoglobin structure
- Hemoglobin contains four polypeptide chains.
- Binding of one oxygen molecule by one subunit affects the oxygen binding of other three subunits.
What are the two types of higher-order structure or symmetry that proteins can have?
Many multisubunit (or, multimeric) proteins have either rotational symmetry or helical symmetry (e.g., virus capsids).
- Human poliovirus has an icosahedral capsid (300 Å in diameter) made up of 240 identical polypeptide subunits.
- Tobacco mosaic virus is rod-shaped, 3000 Å long and 180 Å in diameter, and has right-handed helical filament made up of 2,130 identical polypeptide subunits.
intrinsically disordered proteins (IDPs)
- Function in the absence of a defined 3D structure.
- One third of all human proteins are unstructured or have significant unstructured segments.
- Characterized by high densities of charged amino acid residues such as Lys, Arg, and Glu, and Pro residues to disrupt ordered structured.
- Do not aggregate unlike other proteins because of the lack of hydrophobic core and high charge density.
- Allows the protein to bind to multiple partners because of lack of an ordered structure.
bacteriorhodopsin
- Integral protein
- It absorbs visible light and converts light energy to chemical energy.
- It has seven, very hydrophobic a-helices spanning the membrane.
- Since the surrounding lipid medium is very hydrophobic, membrane proteins have
- Hydrophobic residues exposed to the lipid medium
- Hydrophilic residues buried in the protein interior
- Because of this, membrane proteins unfold or undergo serious structural transitions when removed from membranes
Describe the structure of a ß-barrel.
- Several transmembrane segments form ß-sheets that line a cylinder.
- In addition to hydrophobic residues exposed to lipid medium, the structure is stabilized by the maximal intrachain H-bonding in the protein interior.
- In these structure, polypeptide is more extended than in an α-helix because just seven to nine residues of ß conformation are needed to span a membrane.
ATP-binding cassette (ABC) transporters
- ABC (ATP-binding cassette) transporters use ATP to pump a wide variety of substrates against a concentration gradient.
- One ABC transporter, MDR1, is responsible for tumor resistance to antitumor drugs because it actively pumps the drugs such as doxorubicin, adriamycin, and vinblastine out of the tumor cells.
