膜蛋白和药物转运讲解
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P-GLYCOPROTEIN AND DRUG TRANSPORT
Michael M. Gottesman Chief, Laboratory of Cell Biology, NCI Deputy Director for Intramural Research National Institutes of Health
13% 19%
Digestive System Pancreas & Liver
253,500 59,730
136,060 47,220
54% 79%
Lung and Bronchus
172,570
163,510 95%
Bladder Kidney and Renal Pelvis
63,210 36,160
Mechanisms of Resistance
Overexpressed ABC Fewer Functional
Defective endocytosis
Transporters
UptakeTransporters
DIFFUSION
D DD
D
D
D
D D
D
DFra Baidu bibliotek
D
D
(ABCB1)
D
D D
Pgp
D
D D
ATP binding
ATP binding
ABCC1
ABC G2
Hypothetical Model of Human P-glycoprotein
100
OUT MEMBRANE
IN
200
ATP SITE 300
A
B
700
P
400
C
800
P
900
P 600
P
1 500
POINT MUTATIONS ( ), PHOTOAFFINITY LABELED REGIONS ( ), AND PHOSPHORYLATION SITES ( P )
Ultimate Goal:
To use molecular analysis of human cancers to predict response to specific
therapy To use this information to develop novel
drugs to treat cancer To learn more about cellular pharmacology
• Just as oncogene targets have been catalogued, we need to enumerate all mechanisms of drug resistance in cancer to solve this problem and circumvent resistance
January 18, 2007
Estimated New Cancer Cases & Deaths, 2005
Sites
New Cases Deaths** %
All Sites
1,372,910 570,280 42%
Prostate Breast
232,090 212,930
30,350 40,870
1000
ATP SITE
A
1200 B
C 1100
1280
Structure of E.coli BtuCD, a vitamin B12 transporter.
Locher et al. Science. 2002
20 transmembrane helices
X-ray structure 3.2 A
Structural Organization of an ABC Transporter
Transmembrane Domain
R
\/\/\ ATP-Binding Domain
ABC transporters: Domain organization
ABCB1
TM Domain
TM Domain
13,180 12,660
21% 35%
Genital System, female Lymphoma & Leukemia
79,480 98,550
28,910 43,180
36% 44%
Brain & Nervous System
18,500
12,760
69%
**Vast majority of deaths due to chemotherapy resistance
CA Cancer J Clin, 2005
Mechanisms of resistance to anticancer drugs
Decreased uptake
Reduced apoptosis Altered cell cycle checkpoints Increased metabolism of drugs Increased or altered targets Increased repair of damage Compartmentalization
D
(ABCG2)
D MXR
GS D
D
MRPs
ABCC1-C4
DD
DD
ATP-BINDING CASSETTE
(N-terminal NBD of human Pgp)
390 427
A
556 620
CB
Walker A
ABC linker Walker B D-loop
Y GNSGCGKST LSGGQKQRIAIA ILLLD EA TSALD
and pharmacokinetics of drugs
How Drugs Get Into Cells
Diffusion
D D
D
e.g., vinblastine, doxorubicin
T ransport
D
D
e.g., nucleoside analogs
Endocytosis
D D
e.g., immunotoxins
Increased efflux
Drug Resistance in Cancer
• May affect multiple drugs used simultaneously: known as multidrug resistance (MDR)
• Affects all classes of drugs, including newly designed targetted drugs
ATP binding domains
Substrates and Reversing Agents of Pgp
Michael M. Gottesman Chief, Laboratory of Cell Biology, NCI Deputy Director for Intramural Research National Institutes of Health
13% 19%
Digestive System Pancreas & Liver
253,500 59,730
136,060 47,220
54% 79%
Lung and Bronchus
172,570
163,510 95%
Bladder Kidney and Renal Pelvis
63,210 36,160
Mechanisms of Resistance
Overexpressed ABC Fewer Functional
Defective endocytosis
Transporters
UptakeTransporters
DIFFUSION
D DD
D
D
D
D D
D
DFra Baidu bibliotek
D
D
(ABCB1)
D
D D
Pgp
D
D D
ATP binding
ATP binding
ABCC1
ABC G2
Hypothetical Model of Human P-glycoprotein
100
OUT MEMBRANE
IN
200
ATP SITE 300
A
B
700
P
400
C
800
P
900
P 600
P
1 500
POINT MUTATIONS ( ), PHOTOAFFINITY LABELED REGIONS ( ), AND PHOSPHORYLATION SITES ( P )
Ultimate Goal:
To use molecular analysis of human cancers to predict response to specific
therapy To use this information to develop novel
drugs to treat cancer To learn more about cellular pharmacology
• Just as oncogene targets have been catalogued, we need to enumerate all mechanisms of drug resistance in cancer to solve this problem and circumvent resistance
January 18, 2007
Estimated New Cancer Cases & Deaths, 2005
Sites
New Cases Deaths** %
All Sites
1,372,910 570,280 42%
Prostate Breast
232,090 212,930
30,350 40,870
1000
ATP SITE
A
1200 B
C 1100
1280
Structure of E.coli BtuCD, a vitamin B12 transporter.
Locher et al. Science. 2002
20 transmembrane helices
X-ray structure 3.2 A
Structural Organization of an ABC Transporter
Transmembrane Domain
R
\/\/\ ATP-Binding Domain
ABC transporters: Domain organization
ABCB1
TM Domain
TM Domain
13,180 12,660
21% 35%
Genital System, female Lymphoma & Leukemia
79,480 98,550
28,910 43,180
36% 44%
Brain & Nervous System
18,500
12,760
69%
**Vast majority of deaths due to chemotherapy resistance
CA Cancer J Clin, 2005
Mechanisms of resistance to anticancer drugs
Decreased uptake
Reduced apoptosis Altered cell cycle checkpoints Increased metabolism of drugs Increased or altered targets Increased repair of damage Compartmentalization
D
(ABCG2)
D MXR
GS D
D
MRPs
ABCC1-C4
DD
DD
ATP-BINDING CASSETTE
(N-terminal NBD of human Pgp)
390 427
A
556 620
CB
Walker A
ABC linker Walker B D-loop
Y GNSGCGKST LSGGQKQRIAIA ILLLD EA TSALD
and pharmacokinetics of drugs
How Drugs Get Into Cells
Diffusion
D D
D
e.g., vinblastine, doxorubicin
T ransport
D
D
e.g., nucleoside analogs
Endocytosis
D D
e.g., immunotoxins
Increased efflux
Drug Resistance in Cancer
• May affect multiple drugs used simultaneously: known as multidrug resistance (MDR)
• Affects all classes of drugs, including newly designed targetted drugs
ATP binding domains
Substrates and Reversing Agents of Pgp