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122 Cards in this Set
- Front
- Back
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what makes primary structure |
just peptide bonds |
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secondary structure |
mainly H bonds, |
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3 structure |
Forces stabilizing tertiary structure include |
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what is the most succeptive to heat out of structural forces |
ionic bonds |
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what force succeptive to detergents |
hydrophobic interactions |
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L leptins |
dChaperones?? |
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Aspartyl proteases |
Use aspartate and aspartic acid in their active site, where aspartic acid stabilizes water and aspartate to remove hydrogen from water which is also in the active site HOLD HIM DOWN ILL BEAT HIM |
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Metalloproteases |
use metal usually zinc in the active site and water. the metal holds the water in place so that.. |
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Carbonic acid |
water and carbon dioxide to carbonic acid zinc held in place by 3 His zinc binds water then water loses proton ooptimal ph 8 |
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limiting step of CA |
abstraction of water proton b/c of pka zinc helps lower its pka general base then accepts proton
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what happens when restriction enzymes bind correct DNA |
drastic shape change which bends the dna too |
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what does the bend help with |
the bend creates a pocket for magnnesium to be able to be positioned properly with the water so that water can be activated and cleave |
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methylases |
add the sequence to it. viral DNA can also be methylated if it comes in and the restriction too slow, but if it's too fast then it will be cleaved (the noncognate) |
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type of noncovalent of restriction that is most inportant |
hydrogen bonds between the cognate DNA and the enzyme |
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why is the enzyme antiparallel in active site |
DNA is |
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rxn of ATCase |
aspartate plus carbamoyl phosphate goes to Ncarbamoyl phosphate |
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positive activators of ATCase |
ATP (signals high level of energy in the cell and unequal ratio of pyramidines to purines) atp is purine aspartate is homotropic regulator cooperativity |
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inhibitors of ATCase |
CTP, (hetereotropic allosteric)
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structure of ATCase |
12 subunits, 6 cat 6 reg |
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what is PALA |
manmade inhibitor of ATCase, allosterically. Locks it into R state. a little pala promotes reaction (R state) too much blocks it all binds to the active site
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activation of chymotrypsin |
trypsin cuts at 6 to make active alpha chymo trypsin cuts 15-16 to make pi chymo which is active too and is held together by disulfide it cuts itself polypeptide of 3 small changes large change because without it the active site isnt right |
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alpha-1-antitrypsin |
inhibitor of trypsin and elastase |
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prothrombin |
requires calcium to be held near surface readily converted to thrombin once its there |
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what enables prothrombin to bind calcium |
carboxylated glutamate residues on it |
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what ENYME enables prothrombin to bind calcium |
an enzyme that requires vit K |
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what does vit K do |
it's a coenyzme in a reaction to carboxylate glutamate on prothrombin to allow it to be near surface |
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what are good blood thinners or anticoagulants |
vit K analogs, block vit K sites on enyme, can't be carboxylated, etc |
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Plasmin A |
removes the clot is a zymogen plasminogen activated by tissue tupe activator
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target of antiinfluenza |
r |
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P type ATPases intermediate |
phosphoaspartases |
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what causes first conformational change |
transfer from ATP to aspartate |
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what causes second in ATPase |
hydrolysis of phosphate |
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what binds first in the ABC transporters |
the compound |
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mechanism of ABC |
compound bind, conformational change ATP can now bind eversion bound compound on outside ATP hydrolyzed eversion again
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mechanism of ATCase and how do we know |
u know |
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how does digitalis work |
stops the Na from leaving so no gradient for the Na/Ca to work, then longer forceful contractions too much you just die
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Tetradoxin |
poison from puffer fish blocks Na so no nerve transmission |
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specificity of channel |
size and energy |
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evidence for ball and chain of channels |
treatment of cytoplasm with trypsin leads to permanently pen channel even after depolarization (trims something off) -- N terminal splice varants have altered inactivation kineticsand deleting aa keeps open but adding esynethetic peptide that are thesame as the 42 even tho not part of it restores the inactivation so there must be a clump |
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where is prostaglandid H2 synthase |
the membrane, where arachnoic acid is as well arachidonic acid doesnt have to enter aqueous environment |
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what does asprin do |
inhibits cyclooxygenase activity of the prostaglandid h2 synthase thru transfer of acetyl group vs just blocking it like sialic acid does |
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DFG motif of gleevac?!?!? |
???@??2 |
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how to examine resistance of CML |
test autophosphorylation as well as a downstream one since it shouldnt be there if the thing isnt workin |
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does gleevac bind phosphorylated or unphosphorylated bracbl and why |
idk |
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what mutation in CML causes resistance |
Thr315Ile, steric clashing, drug too big |
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pathways and usages of them |
start with compound (asprin) start with target (gleevac, HIV) |
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measures of drug effiacy |
Kd, Ec50, Ki |
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recognition seq of N glycosylation |
Arg-X-Thr or Arg-X-Ser |
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recogn seq of PKA?? |
?? Arg-Arg-X-Ser-Z |
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absorption measurements |
Lipinski's rules weigh less 500 D less than 5 donors less than 10 acceptors log base 10 (organic)/(water) |
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distribution |
low EC90 and EC50 |
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if drug lasts for a long time in the stomach and short timein intestine what does this mean |
slow acting and less absorbed |
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what is used by hydrophobic compounds to travel in blood |
human serum albumin and diffusion |
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what can you do to see where there is distribution to |
PET |
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what makes a drug that works in vivo not work in real life |
toxicity and ADME |
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modern drug discovery |
high throughput screening combinatorial chemistry structure based design
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problems with strucutre based design |
adme limitations, toxicity, hard to obtain a 3d structure of the enzyme, if we have one usually inactive may be different when active |
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Modifications of current drugs |
asprin modifies both cox1 and cox 2 may be too effective (toxic because completely stops activity) |
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ABL |
non receptor tyrosine kinase |
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bcr-abl |
protooncogene or oncogene?? |
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3 key structural studies on gleevac specificity |
1) known structure of inhibitor bound to similar one 2) solved structure of c-abl with related imatinib molecule |
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examples of P type ATPases |
Ca+ atpase/ gastric H/K atpase |
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couples delta G changes to conformational changes |
ptpe atpases |
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special about SERCA |
keeps 15000 more in than out |
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structure of SERCA |
A P N domain where A is the activator causes conformational change when the aspartate on the P gets phosphorylated N domain binds to NTP they are all coordinated by a number of carbonyls on the transmembrane domain |
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What is the P loop in P type atpases |
P loop is between a1b of the pump it is made up of Gly-X-X-X-Glys-Lys
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What makes up the selectivity filter of K |
TVGYG |
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TVGYG |
signature sequence of selectivity pore of K in restricted part of K |
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Proposed mechanism of tetradoxin effect on Na channel |
It is positively charged so it reacts wiht the neg charged S4! |
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mechanism of lactase permease |
once H goes in, binds to COO- residue on one half, Lactose binds to the sites (1 of them), then it everts, then lactose leaves, then H leaves (ping pong) once H leaves there is eversion.
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structure of lactase permease |
6 TM helices joined together |
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Secondary active |
Not driven by ATP |
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What enzyme requires ATP |
Metalloproteases??? Myosin. |
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what opens voltage gated channels |
the voltage sensing S4 when membranes depolarize moves S4 up and opens the pore |
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What is CFTR |
ABC transporter that is mutated in cystic fibrosis Cl- cant leave water cant move mucus in lungs F508 mutation n NBD1 |
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What structural study done on SERCA helped us find the mechanism |
Phosphorylaspartate analog: showed that the transmembrane shifted and that N and P sites blocked Ca binding sites, |
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Mechanism of SERCA |
Open on cyto side, Ca comes into the two sites ATP comes in, sites are blocked Aspartate on P domain is hydrolyzed ADP released Eversion Aspartate is hydrlolyzed Eversion back to normal |
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Na-K structure |
a2b2 subunits |
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Mechanism of Na/K |
3 Na in from inside Phosphorylation favors eversion to E2 3 Na go out 2 K join dephosphorylation favours E1 2 K released |
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What type of protein transport has carb moiety |
ABC transporters are P-glycoproteins |
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Structure of ABC |
2 ATP binding casettes 2 membrane spanning domains have p loops wthin casettes? |
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mechanism of ABC |
open and close substrate bind allows 2 atp to bind to atp binding casettes eversion out atp hydrlyzed eversion to beginning |
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subunits in K channel |
4 but S1-6 |
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inactive chymotrypsn to active |
causes the formation of the oxyanion hole, catalytic triad, as well as the S1 pocket because of the folding and interactions |
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what kind of proteases are clotting factors |
serine ones (like trypsin) like the same zymogen cascade |
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hwo does EDMA stop blood clottin |
it chelated the ca needed in prothrombin |
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how is prothrombin not active |
it has glutamate which are then turned to gamma |
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what does carboxylating the glutamates in prothrombin do |
makes glutamate a good chelator of Ca+ which makes it go |
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what is needed to carboxylate the glutamates in prothrombin |
Vitamin K |
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What is activated by thrombin to digest factors 5 and 8 and 10 ? |
Protein C |
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how do anticoagulants work |
mimic K analog to prevent the enzyme from carboxylating the glutamates on prothrombin |
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what affects thrombin, f9, 10, 11 and 12 |
antithrombin 3 |
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what activates antithrombin 3 |
heparin which causes formation of the enzyme that makes antithrombin 3 |
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what kind of carb is heparin |
glucasmainoglycan |
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what does TFPI do |
inhibits the extrinsic pathway (no F7) |
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how do you stop proteases if activation is irreversible |
you have ti inhibit them with things like trypsin inhibitor (and antielastase) |
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extrinsic pathway |
TF - > 7 - > 10 |
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what does alpha1 antitrypsin do and what happens if you mutate methionine |
it normally is elastase inhibitor but this switches it to a trombin inhibitor, hemmorhage because not enough thrombin |
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how are they broken down (clots) |
TPA activates plasmin, the serine protease plamin then cuts the connective rods between fibrin free plaminogen slowly activated but plaminogen that is on the fibrin is fast activated heart attacks then can be prevented by quick administration of TPA |
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pseudosubstrate aa sequence |
RRNAI |
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active aa substrate for PKA |
RRxSI or RRxTI and activated by cAMP on reg units |
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how does thrombin activate fibrin cleavage wise |
cuts 4 R-G bonds |
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is zymogen activation irreversible? explain |
yes but they can also be irreversible inhibited antithrombin III irreversibly inactivates thrombin 9 10 11 12 activated by heparin |
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How is it confined to site of injury |
anion surface attracts |
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How is it regulated |
? |
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How is thrombin cascade positive feedback |
it itself regulates 5 and 8 factors |
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what does transglutaminase do |
it cross links glutamine and lysine TO MAKE A HARD CLOT |
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how is E in chymo formed properly in changes |
Amino group of Ile16 interacts with Aspartate 94 to form a salt bridge Forms S binding site and oxyanion hole E is then accomplished by discrete local changes |
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what happens if you smoke |
it modifies antitrypsin so that it isnt effective and it stops binding elastase so elastase eats ur lungs |
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royal family hemophilia |
von willebrand, 8 deficiency so no 9 to 10 (proteases) isolating the 8 makes it so that we can transplant it |
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how are soft clots formed |
thrombin cleaves fibronogen in the center by cleaving off fibrinopeptides |
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how is soft clot formed |
two identical chains with C domain globules with holes ( b and g ) the b has glys-his-arg and g has gly-pro-arg
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what is factor XIII and what is it super important for |
TRANSGLUTAMINASE!!! HARD CLOT!!! LYSINE AND AND GLUTAMINE!!! |
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evidence for subunits of ATcase and zinc???? |
mercaptonal bound to cysteine sulfhydryl ??/ |
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active site of metalloproteases |
Zinc, which assumes pentaacoordinate geometry between His His and Glu ??? , the oxygen of nucleophilic water activated by , and carbonyl oxygen of the substrate to orient it |
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active site of restriction enzymes |
Magnesium bound to 3 water molecules, 2 carboxylates of aspartates, and oxygen of the phosphorous at site of cleaveTT |
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how does the zinc cause restirction to work |
he magnesium ion holds a water molecule in a position from which the water molecule can attack the phosphoryl group and, in conjunction with the aspartate residues, helps polarize the water molecule toward deprotonation. |
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which enzme uses magnesium |
myosins use mg to coordinate the ATP |
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prevention of methylase |
When a methyl group is added to the amino group of the adenine nucleotide at the 5′ end of the recognition sequence, the methyl group's presence precludes the formation of a hydrogen bond between the amino group and the side-chain carbonyl group of asparagine
This asparagine residue is closely linked to the other amino acids that form specific contacts with the DNA. The absence of the hydrogen bond disrupts other interactions between the enzyme and the DNA substrate, and the distortion necessary for cleavage will not take place (it wont kink and hug it) |
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Carbonic anhydrase active |
Zinc++ coordinated by 3 Zincs |
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Mg in active site |
Protein Kinase A (also has Ca++) H/K pump
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solubility of starches |
more branching more soluble because enymes can attack to the reducing ends of branches |
