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MIMS > Molecular Recognition > Flashcards

Molecular Recognition Flashcards

1
Q

What kind of interfaces are there in permanent interactions?

A

Large hydrophobic interfaces

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2
Q

What kind of interfaces are there in transient interactions?

A

Hydrophobic and hydrophilic

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3
Q

How does hydrophobic interaction affect affinity?

A

Increases BUT not specific so use polar or charged groups too

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4
Q

What is Ka? What is Kd?

A

Association constant, dissociation constant

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5
Q

What is fraction bound?

A

[protein:ligand]/[protein]+[protein:ligand]

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6
Q

What is the other eqn for fraction bound?

A

[L]eqm / [L]eqm + Kd

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7
Q

If ligand is in excess, what is the equation for fraction bound?

A

[L]total / Kd + [L]total because L at eqm would be the same as total L

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8
Q

What is Kd?

A

The conc when 50% of protein is bound to ligand

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9
Q

What is Kd of efficient drugs?

A

Lower because they must compete with natural ligand

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10
Q

Why is Kd hard to measure in very high affinity interactions?

A

Need data point below is with very low [protein:ligand] so not possible to measure

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11
Q

What is isothermal titration calorimetry?

A

Measures heat changes when ligand added, keep at constant temp

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12
Q

How do you measure kon and koff?

A

Surface plasmon resonance, immobilise protein and flow ligand over, causes change in refractive index, slopes give on and off rate

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13
Q

What is the structure of the epidermal growth factor receptor?

A

Single alpha helix through the membrane

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14
Q

What does ligand do to EGF?

A

Causes conformational change to expose domain II - two receptors join at domain II (dimerisation state), domain I and III join to form EGF binding site and kinase activated but only one

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15
Q

What does the SH2 domain bind to?

A

Phosphorylated tyrosine and Grb2

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16
Q

What is the structure of an SH2 domain?

A

Antiparallel B sheet and two alpha helices

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17
Q

How does phosphopeptide bind in SH2 domain?

A

As an extended strand

18
Q

What interacts with the negative phosphate group of the SH2 domain?

A

Arg and Lys

19
Q

What are the two binding pockets of an SH2 domain?

A

One to phosphotyrosine, one to side chains from binding peptide

20
Q

What does Sos do to Ras?

A

Changed conformation, bound by large electrophilic interface

21
Q

What does Grb2 do?

A

Recruits Sos

22
Q

Which domains does Grb2 have?

A

SH2 to bind to tyrosine and two SH3 groups to bind to proline and Sos

23
Q

How does Grb2 have such strong interactions with Sos?

A

Binding surface hydrophobic

24
Q

Where does proline from Sos bind to Brb2?

A

Groove in it

25
Q

What causes Ras to swap GDP for GTP?

A

Sos

26
Q

What is the structure of an SH3 domain?

A

5 antiparallel B strands, aromatic residues from hydrophobic patch, binds a lefthanded polyproline helix

27
Q

Why is Ras active with GTP?

A

Forms H bonds with gamma phosphate, downstream effectors recognise its active conformation

28
Q

How does Ras’s “off switch” work?

A

Uses GTPase activating protein, inserts Arg into active site to stimulate hydrolysis

29
Q

What happens when Ras binds to Raf?

A

Forms intermolecular antiparallel B sheet, H bonds and ionic interactions, no contact between Raf and GTP

30
Q

What does Raf contact?

A

One of the main switch regions whose conformation changes when GTP binds to Ras

31
Q

What does Raf phosphorylate?

A

Ser and Thr

32
Q

Why is Raf inactive and how does it activate?

A

Because it loops in on itself, when Ras binds to N terminal region it straightens out and can now phosphorylate other proteins

33
Q

Where does DNA binding specificity come from?

A

H bonds to side chains and base pairs, inserts alpha helix into major groove

34
Q

How do Fos and Jun interact?

A

Spirals with Leu in the centre which fit into major grooves, non-specific ionic interactions with phosphates, specific H bonds with bases

35
Q

How do kinases become inactive?

A

When activation loop blocks active site, phosphorylation moves it so any -ve group would mimic phosphate and cause overactive kinase

36
Q

What is the usual Raf mutation in malignant melanomas?

A

Val > Glu in activation loop so Raf is activated without signal

37
Q

What is fragment based drug discovery?

A

Small molecule drugs are hard to find because need to screen too many, instead start with fragments that work and add functional groups

38
Q

What does Vemurafinib treat?

A

Melanoma

39
Q

What are advantages of small molecule drugs?

A

Designed for good properties, easy and cheap, can enter active sites and transition state mimic, easily go through membrane

40
Q

What are disadvantages of small molecule drugs?

A

Can’t inhibit protein-protein interactions because flat surface and few pockets, high failure rate because of unexpected side effects

MIMS (8 decks)

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