LEC3: Protein Structure and Ligand Binding Flashcards Preview

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Flashcards in LEC3: Protein Structure and Ligand Binding Deck (32):
1

why is the binding of a ligand to its binding partner not a permanent interaction? 

because binding sets off a signaling pathway - do not want this always turned on 

need binding to re-occur to signal again

2

For a drug that binds to a receptor to be efficacious, should it have a lower or higher KD than the natural ligand? Why? 

drug should have a lower KD

because KD is dissociation constant - so a lower KD means greater affinity

3

How would removing the tetramerization domain from a protein that forms a four-subunit complex affect its function? 

it woudl become nonfunctional or less effective?

4

Explain why cooperative binding of oxygen to hemoglobin is important for the normal transport of oxygen from lungs to tissues. 

because it allows for most efficient delivery of oxygen to tissues

5

What is an allosteric effector?

molecule that binds to a protein on 1 site, causing a conformational change in the protein that affects its fxn at a distant site

6

what is tertiary structure of a protein? what does it enable?

the overall 3D conformation of a protein 

enables protein to become function 

i.e. amino acid side chains in a particular region of the protein can form a binding pocket for a ligand

7

what is a ligand, and what does it do? examples of types of ligands? 

ligand: molecule that binds reversibly to specific site in proteins, with extremely high specificity 

protein, lipid, small molecules, ions, gases

8

what is the beta-adrenergic receptor?

what binds to what? 

what is the effect? 

example of a ligand-receptor interaction 

hormone, epinephrine (aka adrenaline) binds to its cell surface receptor, the beta-adrenergic receptor 

b-adrenergic receptor is a transmembrane protein w/ 7 membrane-spanning regions of alpha-helices 

epinephrine-receptor binding activates signaling pathway that controls: blood prssure, cardiac output, breakdown of energy stores

9

what is the equilibrium reaction re: ligand-binding partner? 

protein (P) + ligand (L) \rightleftarrows (PL) 

Association: P + L \rightleftarrows PL 

Dissociation: PL \rightleftarrows P + L

KD = [P] [L] / [PL] 

 

10

what is KD? definition, meaning 

what does a low KD mean? 

KD: is the dissociation constant for the dissociation reaction between a ligand & its binding partner 

the concentration of the ligand at which 1/2 of the protein is bound to the ligand 

lower KD = higher affinity of ligand for protein, because it takes smaller amt of ligand to 1/2 saturate the binding partner

11

what is oxygen-hemoglobin binding an example of?

ligand binding

it's reversible

12

what is the structure of adult hemoglobin?

4 globin chains: 2 alpha-globin chains + 2 beta-globin chains

each chain has heme as a tightly bound prosthetic group

 

13

how does oxygen bind to hemoglobin?

ferrous iron (Fe2+) in heme group can form 6 potential bonds

oxygen binds to Fe2+ in heme group and it H-bonds w/ histidine in globin 

14

what is the structure of myoglobin?

only 1 subunit, rather than a quarternary structure, like hemoglobin 

has oxygen-binding site 

 

15

how do oxygen-hemoglobin bind? what does this mean? what does it enables?

example of cooperative binding/allosteric effect/allosteric binding

binding of an oxygen molecule to 1 heme group increases oxygen affinity of remaining heme groups in the same hemoglobin molecule (4th oxygen has 100x affinity as 1st)

enables hemoglobin to very efficiently combine oxygen in the lungs & release it into the tissues 

16

how much of oxygen from lungs by myoglobin, hemoglobin, or hypothetically no cooperative binding oxygen is released into tissue?

what does this demonstrate?

what is the shape of this relationship's curve?

myoglobin: 7%

hemoglobin: 66%

hypothetical: 38% 

demonstrates that cooperative binding allows hemoglobin to most efficiently uptake oxygen from lungs, release it in the tissues

SIGMOIDAL relationship

17

in which state does hemoglobin bind to oxygen? when doesn't it bind to oxygen?

binds in the relaxed (R) state

does not bind in the taut (T) state  

 

18

explain this:

 

Q image thumb

binding of oxygen to hemoglobin

partial pressure of oxygen pO2 (torr) (x) vs. fractional saturation of hemoglobin (y)

when binding occurs in a cooperative manner, plot produces a sigmoidal curve 

cooperative binding allows hemoglobin to become completely saturated w/ oxygen in the lungs, release it in the tissues

19

what are allosteric effectors? 

molecules that bind to a protien on a site, & cause a conformational change in the protein that affects its function at a distant site

20

what molecules are allosteric effectors of oxygen-hemoglobin interaction?

1) oxygen itself affects binding of oxygen thru cooperative binding

2) Bohr effect: Low pH 

3) High CO2

4) 2,3-biphosphoglycerate (2,3-BPG)

21

What is the Bohr effect? How does it work?

High concentration of dissolved COshifts equilibrium toward bicarbonate plus protons, aka lowered pH

Lowered pH causes decrease in affinity of hemoglobin for oxygen (therefore increased KD)

This effect allows more oxygen to be released from hemoglobin in active tissues where pH is low

22

what is this? 

 

Q image thumb

Bohr effect

higher CO2 > lowered pH > increased KD / less hemoglobin-oxygen affinity > more oxygen released to O2-deficient tissues

23

how does CO2 have an allosteric effect on hemoglobin?

when does this occur? 

CO2 can bind directly to hemoglobin, stabilize a conformation w/ a lower affinity for oxygen

occurs in conditions of lower pH, were KD is higher

allows for more release of oxygen into tissues (88%)!

24

what is 2,3-BPG? its allosteric effect on hemoglobin? the result?

2,3-BPH is a highly negative molecule, a metabolic product of glucose breakdown 

it binds to positive part of B-chain of hemoglobin 

binding of 2,3-BPG decreases the affinity of hemoglobin for oxygen 

 

25

what pathological conditions does 2,3-BPG matter for? why?

high levels of 2,3-BPH in individuals w/ anemia or chronic hypoxia due to lung disease

2,3-BPH causes decreased hemoglobin-oxygen affinity, aka

presence of 2,3-BPH results in relase of oxygenf rom hemoglobin at higher partial pressures of oxygen

26

how does 2,3-BPG impact individuals at high altitude?

2,3-BPH increases in reponse to decrease in partial pressure of oxygen in the air 

so it allows adaptation at high altitudes

presence of 2,3-BPH results in relase of oxygenf rom hemoglobin at higher partial pressures of oxygen

27

is hemoglobin structure the same throughout development?

no

diff types of hemoglobin are expressed at diff times during development

28

what is the structure of fetal hemoglobin (HbF)?

what is its affinity for oxygen like re: adult hemoglobin (HbA)

HbF= 2 alpha-globin chains, 2 gamma-globin chains 

does not bind strongly to 2,3-BPH, therefore has a higher affinity for oxygen than HbA

means oxygen is efficiently transferred from maternal RBC > fetal RBC

29

explain this: 

 

Q image thumb

fetal hemoglobin does not bind 2,3-BPG 

it therefore has a higher affinity for oxygen than adult hemoglobin 

it therefore transfers O2 more efficiently to RBC

O2 flows from maternal oxyhemoglobin > fetal deoxyhemoglobin

30

genetic basis for sickle cell anemia?

single ntd change from in beta-globin gene 

results in single amino acid change from glutamate to valine in beta-globin protein 

glutamate = positively charged, usually on outside, vs valine = hydrophobic, usually in center of globulin

valine on outside of 

31

why do sickled cells manifest?

amino acid change in B-globin protein from glutamate to valine promotes polymerization of variant hemoglobin (HbS) b/c of hydrophobic interactions btwn B-globin subunits per valine

HbS polymerization produces long fibers, which distory shape of RBC into curved, sickled appearance

32

how does RBC change shape in sickle cell anemia? what is the result?

usually flexible, compact, round RBC can go through capillaries easily

sickled RBC cannot, clogs small capillaries 

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