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AnnouncementAnnouncement

I am Hyun-Soo Cho, in Biology Department.

This course is Biophysics,

(4) Grading: (4) Grading: Mid exam (35%) + Final exam (35%) + Presentation (15%) + attendance (5%) + Quiz (10%) Mid exam (35%) + Final exam (35%) + Presentation (15%) + attendance (5%) + Quiz (10%)

(3) Assignment (homework): (3) Assignment (homework): Please read your textbook before or/and after each class Please read your textbook before or/and after each class

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(5) Participating in this Biophysics Course (5) Participating in this Biophysics Course Thanks everyone for your interest on this class Have good manners : No cell phone (no message), No chatting I hope you would keep your honor during this course

Thanks everyone for your interest on this class Have good manners : No cell phone (no message), No chatting I hope you would keep your honor during this course

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(6) Interviewing with me (6) Interviewing with me You must see me during this course at least one time My office hours: AM 10:00-12:00 on Friday How: First, Contact me by E-mail or telephone E-mail address: [email protected], 2123-5651

You must see me during this course at least one time My office hours: AM 10:00-12:00 on Friday How: First, Contact me by E-mail or telephone E-mail address: [email protected], 2123-5651

Protein Structure and Function

CHAPTER1. From Sequence to Structure

1-0. Overview : Protein Function and Architecture

Figure 1-1. Four examples of biochemical functions performed by proteins


Figure 1-1. Four examples of biochemical functions performed by proteins

Sheet & strand


Figure 1-2. Levels of protein structure illustrated by the catabolite activator protein

1-1. Amino Acids

Figure 1-3. Amino-acid structure and the chemical characters of the amino-acid side chains

Absolute Configuration : S

Left, Counter-Clockwise

Absolute Configuration : R

Right, Clockwise

Structure and Stereoisomerism of a-Amino Acids

Only L-amino acids are constituents of

proteins.

R : functional group (side chain)

Ca : a-carbon (chiral)NH3+ : amino groupCOO- : carboxyl group

1-1. Amino Acids

Figure 1-3. Amino-acid structure and the chemical characters of the amino-acid side chains

The amino-acid side chains have different tendencies to participate in interactions Hydrophobic residues: van der Waals interactions – tendency

to avoid contact with water and pack against each other hydrophobic effect

- Ala & Leu are strong helix-favoring residues, Proline are not because its backbone nitrogen isn’t available for H-bond

- Aromatic side chain of Phe participates in weakly polar interactions

Hydrophilic residues : Hydrogen bonds to one another, to peptide backbone, to polar organic molecules, and to water.

- pKa shift: Asp & Glu (57 in hydrophobic interior or nearby (-) charge), Lys (106 in ?)

- His: most versatile, most often found in enzyme active sites, pKa is 6, neutral, proton donator and acceptor

- Arg: completely protonated at neural, compared to Lys?

- Cys: common in enzyme active site, most powerful nucleophile. Compared to Ser?

Amphipatic residues : both polar and nonpolar character

- Lys: hydrophic charged region, long hydrophobic region (methylene) involved in van der Waals interactions with hydrophobic side chains

- Tyr: pKa is 9, in some enzyme active site, hydroxyl group can be donor and acceptor of H-bond. Aromatic ring can form weakly polar interactions

- Trp: similar to Tyr, indole amide hydrogen don’t ionize.

- Met: least polar among amphipatic residues, thioether sulfur is excellent ligand for metal ions.

van der waals interaction

- caused by transient dipoles, the momentary random fluctuation in the distribution of the electrons of any atoms

Hydrophobic Effects?

1-2. Genes and Proteins

Figure 1-4. The genetic code

The genetic code is degenerate

Figure 1-5. The flow of genetic information in prokaryotes (left) and eukaryotes (right)


SplicingAnd ?

Alternative splicing can lead to truncated proteins, proteins with different stretches in the middle, and frameshifts.

Coding sequences can also be modified by RNA editing; some nucleotides can be changed and additional nucleotides inserted into the mRNA sequence before translation.

Genetic code organization Single-base changes (single-nucleotide

polymorphism) in the third position in a codon produce the same amino acid. Changes elsewhere in the codon produce a different amino acid, but with the same physical-chemical propherties. The second base specifies if the amino acid is polar or hydrophobic. Conservative substitutions.


Figure 1-6. Table of the frequency with which one amino acid is replaced by others in amino-acid sequences of the same protein from different organisms

Figure 1-7. Peptide bond formation and hydrolysis

1-3. The Peptide Bond

Figure 1-8. Schematic diagram of an extended polypeptide chain


Resonance of peptide bond- Polarity, Dipole moment- partial double-bond character

Figure 1-9. Extended polypeptide chain showing the typical backbone bond lengths and angles


Ramachandran plot

Figure 1-10 Table of the typical chemical interactions that stabilize polypeptides

1-4. Bonds that Stabilize Folded Proteins

1 kcal = 4.2 kJ

Folded proteins are stabilized mainly by weak noncovalent interactions

Figure 1-11. Ramachandran plot

1-5. Importance and Determinants of Secondary StructurePeptide back bone C=O and N-H tend to hydrogen bond with one another, which result in the secondary structure. Especially in the interior of proteins.

Rotational Properties of Peptide Bonds

: the angle of rotation about the bond between the nitrogen and the a-carbon

y : the angle of rotation about the a-carbon and the carbonyl carbon

Peptide bonds are rigid…But,

the bonds containing the a-carbon between two peptide bonds

can be rotated from -180o to +180o.

Figure 1-12. Typical beta turn

1-5. Importance and Determinants of Secondary Structure

Prediction of secondary structure elements from a. a sequence is accurateto only about 70%. convenient way of fold classification

N

N+3

beta turn, reverse turn, hairpin turn

Figure 1-13. The alpha helix

1-6. Properties of the Alpha Helix

N

N+4

Figure 1-14. Table of helical parameters


Lipid bilayer thickness? 30A. To span the cell membrane, how long helix?at least 20 residues long helix All helices in real protein structures are right-handed. Why?

because of steric hindrance caused by L-configuration

Helix dipole increase with increasing length of the helixAt the N-terminal ends of helices negative side chain

Figure 1-15. View along the axis of an idealized alpha-helical polypeptide


Alpha helices can be amphipathic, with one polar and one nonpolar face

Figure 1-16. The structure of collagen


Collagen : bone, tendon, ligament and blood vesselEvery third residue, glycine (GlyXY)n, X & Y proline-Proline lacks N-H groups, hydroxylation!

1) Special examples of -helix

•Collagen: the most abundant protein of mammals, main

fibrous component of skin, bone, tendon, cartilage, and

teeth. ( 피부미용 )

Coiled-coil protein •Structural support for Cells and Tissues

-keratin: left-handed superhelix of two right-handed

helices.

from wool & hair, intermediate filaments in cytoskeleton,

muscle protein (myosin & tropomyosin)

Heptad repeats; Every seventh residue in each helix, Leu

holds two helix by van der Waals interactions

disulfide bond crosslinks: fewer – flexible, more – harder

(horns, claws etc)

2) Special examples of -helix

Figure 1-17. The structure of the beta sheet

1-7. Properties of the Beta Sheet

Figure 1-18. Two proteins that form a complex through hydrogen bonding between beta strands (the Rap-Raf complex, PDB 1gua)


No Plain b-sheetOnly twisted b-sheet.Why?

Stability & integrity of b-sheet depends on # of b-strands

Figure 1-19. Beta barrel ; closed cylinder, retinol-binding protein


strands usually have a pronoucedright-handed twist, due to steric effectsarising from the L-amino acid configuration.

Figure 1-20. Table of conformational preferences of the amino acids

1-8. Prediction of Secondary Structure

A-helices predictionIs easier than b-sheet

Figure 1-21. An example of secondary structure prediction

1-8. Prediction of Secondary Structure

Figure 1-22. Folding intermediates

1-9. FoldingThe structure of a protein is directly determined by its primary structure

Figure 1-23. Highly simplified schematic representation of the folding of a polypeptide chain in water

1-9. Folding

Competition between self-interactions and interactions with water drivesProtein folding

Computational prediction of folding is not yet reliable Ab initio method - Equilibrium conformation is the global free-energy minimum

- potential energy parameter is accurate (H-bond, van der Waals etc)

- key intermediates?

- oligomerization can not be addressed although very many globular proteins are oligomeric.

Protein folding funnel

The hydrophobic environment of a membrane permits only all-helical and all-beta-barrel integral membrane• The polar amide and carbonyl group should hydrogen

bond to

one another because water can’t involve in H-bonds

Figure 1-24. Comparison of the structures of triosephosphate isomerase and dihydrofolate reductase

1-10. Tertiary Structure

The condensation of multiple secondary structural elements leads to tertiary structure•Two proteins with similar secondary structure elements but different tertiary structures

Figure 1-25. Variable loops

1-10. Tertiary Structure - loops

Found at the surface of protein and Exposed to the solvent

Sites for protein recognition, ligandBinding and membrane interaction

Often mutation sites without changing the core structure

Often move as rigid bodies because their side chain pack together

Figure 1-26. Porcine pancreatic elastase showing the first hydration shell surrounding the protein

1-10. Tertiary Structure• Protein crystals contain more than 50% waters in their volumn• hydration shell• a few water inside the protein makes important interactions as part of the tertiary structure

Figure 1-27. Cut-away view of the interior of a folded protein


The atoms are packed as closely as in a solid. A few cavities and small channels provide some flexibility.

Packing by ionic bonds, H-bonds, and van der Waal interactions.

Packing types

Figure 1-28. Packing motifs of a helical structure


The protruding side chains of one helix fit into grooves along the surfaceof the other helix: ridges and grooves

Figure 1-29. A segment of a simulated membrane bilayer

1-11. Membrane Protein Structure

H-bond in a completely nonpolar environment are considered stronger than in water

Figure 1-30. The three-dimensional structure of part of the cytochrome bc1 complex


Polar side chains interacting with polar head group of the lipids and each other

Hydrophobic side chain

helices are the most common secondary structure in membrane proteins

Figure 1-31. Hydropathy plot of the Rhizobium meliloti protein DctB


Average hydrophobicity of an eight-residue along the sequence: hydrophathy

Prediction of membrane helices; 20 consecutive hydrophobic residues

Figure 1-32. The three-dimensional structure of the all-beta transport protein FhuA

1-11. Membrane Protein Structure• Membrane sheet prediction is difficult because of various strands tilt (above 8-9 a.a)• all sheet are antiparallel sheet with short polar turns• all barrel: hydrophobic side chains in surface, polar side chain inside of the barrel

common in channel

How about a mixed structure of sheet and helix?

Figure 1-33. Three-dimensional structure of the bacterial potassium channel


•View looking down the channel

•The pore-forming loop, 2 K+ ions

• Nobel prize in chemistyr 2003 - Roderick Mackinnon (kcsA K+ channel) - Peter Agre (water channel)

"for structural and mechanistic studies of ion channels"

Roderick Mackinnon succeeded in determining the first high-resolution structure of an ion channel, the kcsA K+ channel from streptomyces lividans.

The Nobel Prize in Chemistry 2003The Nobel Prize in Chemistry 2003

Water channel and ion channel

13.6 Specific channels increase the permeability of some membranes to water

-Some tissues need to transport water.

-kidney, secretion of saliva and tears.

※ Aquaporin (Peter Agre in red-blood-cell membrane)

-Water channel. 24kda membrane protein

-6 membrane spanning helices.

-Positive residues in the center prevent the transport of protons through

aquaporin; maintain proton gradients

Ion channel

Potassium and sodium ion

The atomic radius K+ is 1.33 Å and that of Na+ is 0.95 Å .

For the potassium ions the distance to the oxygen atoms in the ion filter is the same as in water.

The sodium ions, which are smaller, do not fit in between the oxygen atoms in the filter. This prevents them from entering the channel.

The different kinds of K+ channels gating (opening)

• ligand gated

- dependent on the intracellular Ca2+ concentration

- the level of certain G-protein subunits in the cell

- cytoplasmic or extracellular domains for binding ligands.

• voltage gated

- the membrane voltage-dependent.

- integral membrane domains for sensing voltage differences.

The Structure of the Potassium Channel

four usually identical subunits that encircle with four-fold symmetry

→ inner, outer, pore α -helix

Molecular surface of KcsA and contour of the pore

the entire internal pore

a pore helix (red) and a selectivity filter (gold). Blue mesh shows electron density for K+ ions and water along the pore.

The ion conduction pore of K+ channelsThe ion conduction pore of K+ channels

The ion conduction pore of K+ channelsThe ion conduction pore of K+ channels

K+ channels conduct K+ ions specifically because the selectivity filter contains multiple binding sites that mimic a hydrated K+ ion’s hydration shell. Potassium channels achieve high conduction rates by exploiting electrostatic repulsion between closely spaced ions and by coupling the conformation of the selectivity filter to ion binding within the filter.

Selective ion conduction

Figure 1-34. Illustration of the ordered arrays of water molecules surrounding exposed hydrophobic residues in bovine pancreatic ribonuclease A

1-12. Protein Stability : Weak Interactions and Flexibility

Water’s role in weak interactions1.Small enthalpy difference.

2. Hydrophobic effect – entrophy(nonpolar groups in water tend to be Surrounded by a cluster of water mols)

•Folding decrease the entropy of the proteins; but increase of water entropy is much bigger (hydrophobic effect)

The folded protein is a thermodynamic compromise •Stability is a net loss of free energy (entropy + enthalpy)Free energy difference between the folded and unfolded states; ~21-42kJ/mole, marginally stable.

Figure 1-35. Computed circular dichroism spectra for the evaluation of protein conformation


• CD shows protein conformation.

• Denaturants (urea, guanidinium hydrochloride, SDS) competes forH-bonds with polar groups of the back bone and side chains.

• Features of themophilic proteins - more salt bridges - more hydrophobic interactions & shorter loops

Protein structure can be disrupted by a variety of agents

Figure 1-36. Results of a molecular dynamics simulation of two interacting alpha helices


All chemical bonds are flexible because ofVibration and rotation

Proteins are much more flexible because of weak interactions to break and reform frequently– Thermal fluctuation is essential for protein function (up to a few angstroms)- Adjust to the binding of ligand or substrate- Water penetration into the interior of the protein

The marginal stability of protein tertiary structure allows proteins to be flexible

Figure 1-37. The structure of the small protein bovine pancreatic trypsin inhibitor, BPTI

1-13. Protein Stability : Post-Translational Modifications

1.Disulfide bond between cysteine side chains-Oxidation of two sulfhydryl groups in ER- not found in most intracellular proteins, but common in secreted proteins

Covalent bonds can add stability to tertiary structure

Figure 1-38. Stabilization by coordinate covalent bonds


2. Coordinate covalent bonds-Coordination of a metal ion to side chains or water molecules- Ca2+ , Zn2+ most common -removal of the metal ions can leads to denaturation (EDTA)

Figure 1-39. Examples of stabilization by cofactor binding

1-13. Protein Stability : Post-Translational Modifications3.Organic or organometallic cofactor at the active site

Pyridoxal phosphate in D-amino acid aminotransferase Heme iron in myoglobin

Methionine S and heme iron in Cytochrome CPorphyrin cofactor - covalent bonds

PQQ in polyamine oxidases

Figure 1-40. Table of post-translation modifications affecting protein stability


Glycosylation at serine, threonine or asparagine residues-N-glycosylation site : NxS/T motif-Most important for protein stability, folding, protein-protein recognition(blood cell surface proteins, prevent cells from sticking to one another, cell walls)

-Deglycosylation can lead to unfolding or to aggregation. Stability change!-Generally not alter the tertiary structure of a protein, Crystal Structure?

Phosphorylation and N-acetylation are reversible and conformational switches

Histones or DNA methylases & Demethylases (JMJD2A, LSD1)

Histone acetylation & deacetylation(CBP, HDACs)

Each histone is organizedin two domains, a characteristic ‘histone fold’ and an unstructuredN-terminal ‘tail’. The histone-fold domains constrain theDNA in a central core particle and, thereby, restrict access ofDNA-binding proteins.

This histone tail is a flexible amino terminus of 11-37 residues.

Several positively charged lysine side chains in the histone tail may Interact with linker DNA, and the tails of one nucleosome likely interact with Neighboring nucleosomes higher-order coiling.

The histone tail lysine, especially those in H3 and H4, undergo reversible acetylation and deacetylation by enzymes such as CBP (P300) and HDACs

In the acetylated form, the positve charge of the lysine e-amino group is neuralized. This eliminate its interaction with a DNA phosphate group.

So the greater the acetylation of histone N-terminus, the less likely chromatinis to form condensed 30-nm fibers and possibly higher-order folded structures.

Sites of Histone Tail Modifications

Epigenetics edited by Allis et al. (2007)

Lac repressor tetramer binding to DNA

1-14. The Protein DomainGlobular proteins are composed of structural domains

-Domain is a structural and functional unit composed of generally continuous amino acids (50~200 a.a.)-Domains have hydrophobic cores

Tetramerization and DNA-binding domain

Alanine racemase

Interuption!

Figure 1-43. Structures of thioesterase and thioester dehydrase

1-14. The Protein Domain

Multidomain proteins probably evolved by the fusion of genes that oncecoded for separate proteins-A single gene is assumed to have been duplicated in tandem-The more ancient the gene duplication, the more time for mutation to happen- examples

Two subunits

Figure 1-44. Structure of gamma-crystallin, eye-lens protein


Two nearly identical domainsGene duplication within a single structural domain

Figure 1-45. Structures of tryptophan synthase and galactonate dehydratase


The number of protein folds is large but limited

- Protein folds are used repeatedly in different combinations

Figure 1-46. Schematic diagram of the domain arrangement of number of signal transduction proteins

1-15. The Universe of Protein Structures

Proteins are grouped into families on the basis of the domains, whose functions are classified. Tempting but not the all case.

Kinases, hydrolase

SH2: phospho-tyr, SH3: proline-richPH: bind to membrane

Figure 1-47. Structures of aldose reductase (left) and phosphotriesterase (right)

1-15. The Universe of Protein Structures

-use NADPH to reduce sugars. -hydrolyze phosphate goups

Common TIM barrel of eight-stranded parallel beta barrelBut different biochemical functions; exceptional case!

Figure 1-48. Structures of aspartate aminotransferase (left) and D-amino acid aminotransferase (right)

Both enzymes catalyze the same reaction but they have no structuralSimilarity to each other in a.a. sequence and tertiary structure

The modular structure of protein structure allows for sequence insertions and deletions

Q: How long polypeptides domains can be inserted in or deleted from a protein structure without disrupting structure?

Q: Insertions and deletions nearly always occur in the surface loop. Why?

Figure 1-49. Zinc finger motif

1-16. Protein Motifs may be defined by their primary sequence or by the arrangement of 2nd structure elements

Protein Motif• sequence motif/structural motif• functional motif

Zinc finger motif – sequence motifCXX(XX)CXXXXXXXXXXXXHXXXH

Figure 50. Helix-turn-helix Four-helix bundle motif

1-16. Protein Motifs

• Functional motif

Human growth hormone

• Structural motif

Figure 1-52. Catalytic triad of serine protease (a) subtilisin, (b) chymotrypsin.

1-16. Protein Motifs

•Identifying motifs from sequence is not straightforward.

•Functional motifs are detected from the structure rather than the sequence.

1-17. Alpha Domains and Beta Domains

Group domain folds into 5 classes, based on the predominant secondary structure.

•Alpha domains:

•Beta domains: only beta sheet

•Alpha/beta domains: beta strands with connecting helical segments

•Alpha+beta domains: separate beta sheet and helical regions

•Cross-linked domains: secondary structure are stabilized by disulfide bonds or metal ions

Myohemerthrin Myoglobin

1-17. Two common motifs for alpha domains

Four-helix bundle- Common in hormones

Oxygen-strage protein in marine worms4 helices, 20 degree tilt,

Oxygen-strage protein8 helices, 90 and 50 degree tiltHydrophobic pocket for organometalic

Globin fold

Neuraminidase beta-propeller domain Pre-albumin

1-17. beta domains contain strands connected in two distinct ways

1. Connected to adjacent strand;Up-and-down structural motif

2. Connected to 3rd strand; Greek key motif

Figure 1-56. Immunoglobulin

1-17. Antiparallel beta sheets can form barrels and sandwiches

All-beta domains contain antiparallel beta strcuture, the strands of which are connected with beta turns and larger loops

Beta sandwiches-Antiparallel beta sheets pack against each other; one face of sheet orients to solvent, and the other face orient toward the hydrophoic core.-two greek-key motifs

Figure 1-59. Bacteriochlorophyll A protein

1-17. Beta Domains; variation

Jelly roll: variation of beta sandwichFibrous protein silk: two-sheet structureSequence: GAGSGAGSGAGSG

Figure 1-60. Crossover connection between parallel beta strands

1-18. Alpha/Beta, Alpha+Beta and Cross-Linked Domains

In alpha/beta domains, each strand of parallel beta sheet is usually connected to the next by an alpha helix giving rise to beta-alpha-beta-alpha units

Right-handed twist of the beta sheetprefered the right-handed crossover topology

Right-handed crossover connection

left-handed crossover connection

Figure 1-61. Alpha/beta domains

1-18. Alpha/Beta Domains

Two major families of domains: barrel and twist

• barrel, TIM barrel Triosphosphate isomerase•Parallel & Nonpolar beta strand followed by a amphipathic Alpha helix, repeated eight times

• twist, Semi-aldehyde dehydrogenaseparallel strands protected from water by helices coating Nucleotide-binding fold

Figure 1-62. Alpha+beta saddle, TATA-binding protein

1-18. Alpha+Beta Domains

Alpha+beta domains have independent helical motifs packed against beta sheet; segregated!

MHC

Figure 1-63. Disulfide-linked protein

1-18. Cross-Linked Domains

In small irregular domains, disulfide bridges and metal ions form cross-links

Scorpion toxin-Very stable to proteolyticDigestion and heat denaturation-No hydrophobic core but stabilizedby 4 disulfide bonds

Figure 1-64. Zinc finger

1-18. Cross-Linked Domains

2 histidines and 2 cysteines Coordinate a zinc ion.

Too small to have hydrophobic core

The most abundant one in the human

Figure 1-65. Schematic representations of different kinds of oligomers

1-19. Quaternary Structure : General Principles

Oligomers: composed of more than one polypeptide chainsubunits

Most common

Hemoglobin

Figure 1-66. “Open-book” view of the complementary structural surfaces that form the interface between interleukin-4 (left) and its receptor (right)

1-19. All specific intermolecular interactions depend on complementarity

Shape complementarity is necessary for large number of weak interactionsand to maximize the strength of interactions ((H-bonds and van der Waals)

Protein surface is irregular. What doest enable proteins to bind specific molecules?

Figure 1-67. Coiled-coil alpha-helical interactions

1-19. Shape complementarity

For stable complex,Bond strength should be greater than about 15-20 kJ/mole.So shape complementarity is necessary.

tropomyosin

Figure 1-68. Peptide-peptide interactions in the coiled coil of the leucine zipper family of DNA-binding proteins

1-19. Shape complementarity

Transcription factors of leucine zipper

On monomers are disorderedBut fold on dimerization by hydrophobic Interactions

N N

C C

Heptad repeat

Figure 1-69. Water molecules at a subunit interface

1-20. Quaternary Structure : Intermolecular Interfaces

Formation of intermolecular interfaceIs mediated by hydrophobic interactions,Hydrogen bonds and salt briges Including metal-ion ligation and disulfide bond

Hemoglobin: several intersubunit salt bridgesDepending on pH, alter the relative orientation of the subunits & the affinity for oxygensVery stable oligomers tend to bury a large

hydrophobic surface area between subunits while polar interactions more easily break

Figure 1-70. Oligomerization by beta sheet formation


Rap Raf

Figure 1-71. Sickle-cell hemoglobin

1-20. Inappropriate quaternary interactions induce disease

Hydrophobic patch from the mutation in 2 subunit (Gln Val)Thick fiber

Figure 1-72. Dominant-negative phenotype resulting from hydrophobic interactions between mutant and normal subunits of a dimeric protein


Oligomeric proteins are more susceptible to disruption by mutation

Monomeric proteins; loss of function occurs in homozygous conditionsOligomeric proteins: loss of function may occur in heterozygous conditionsWhy oligomer in terms of evolution?

Figure 1-73. The human growth hormone-receptor complex

1-21. Protein assemblies built of identical subunits are usually symmetric

Asymmetric complex

Figure 1-75. Interactions underlying different geometric arrangements of subunits

1-21. Protein assemblies built of identical subunits are usually symmetric

Asymmetric unit isProtomer.

Figure 1-74. Examples of quaternary arrangements observed for oligomeric proteins

1-21. Quaternary Structure: Geometry

Figure 1-74. Examples of quaternary arrangements observed for oligomeric proteins

1-21. Quaternary Structure: Geometry

rhinovirus proteasome

Figure 1-76. Table of protein motions

1-22. Proteins are flexible

Figure 1-77. Triosephosphate isomerase

1-22. Conformational fluctuations in domain structure tend to be local

Common ligand-induced conformational change is the lid-like movement of a polypeptide segment to cover a ligand-binding site.

Figure 1-79. T4 lysozyme

1-22. Protein Flexibility

Alternate between distinct conformations

Free-energy barrier

Figure 1-80. Aspartate aminotransferase, open and closed forms

1-22. Protein Flexibility

Driving force is provided by ligand-proteinInteractions

Induced fit

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