Deep Cholesterol Binding Sites    Anthony Lee - University of Southampton

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Deep Cholesterol Binding Sites

• Introduction
• GPCR Class A
• Rhodopsin and Opsin
• GPCR Class B
• GPCR Class C
• GPCR Class F
• Adiponectin Receptor
• Ion Channels
• Porins Etc.
• Transporters
• Other Membrane Proteins

Interfacial Cholesterol Binding Sites

• GPCR Class A [Part 1]
• GPCR Class A [Part 2]
• GPCR Class B
• GPCR Class C
• GPCR Class F
• Adiponectin Receptor
• TRPA-TRPN channels
• TRPP-TRPV channels

Deep Cholesterol Binding Sites on Mammalian Membrane Proteins

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Ion Channels

[Letters refer to subunits as given in the PDB file, followed by the TM helix number; P Pore Helix; Units of E, kcals/mol with molar concentration units]

E	Donor		Acceptor		Local Residues (within 3 Å of a cholesterol –OH group)
Potassium Channels
Two-pore domain TWIK-1 human, 3ukm
-8.3	Chl	OH	Thr225 [A P2]	OG1	Ser224  [A P2]	Thr225 [A P2]
-8.2	Chl	OH	Thr225 [B P2]	OG1	Thr117 [A P1]	Ser224 [B P2]	Thr225 [B P2]
-7.6	Chl	OH	Leu115  [A P1]	O	Leu115 [A P1]	Ile142 [A2]
Two-pore domain TRAAK in non-conductive down state, human, 3um7
-8.4	Chl	OH	Thr238 [B P2]	OG1	Thr129 [A P1]	Thr237 [B P2]	Thr238 [B P2]
-8.1	Chl	OH	Ser45 [B1]	OG	Tyr42 [B1]	Ser45 [B1]	Gly46 [B1]
-7.0	Chl	OH	Thr212 [B3]	OG1	Leu207 [B3]	Leu211 [B3]	Thr212 [B3]
-7.0	Chl	OH	Leu151 [B2]	O	Leu151 [B2]
-6.5	Chl	OH	Leu208 [A3]	O	Leu208 [A3]	Pro213 [A3]
Two-pore domain TRAAK in non-conductive down state in K+, human, 4wff
-6.6	Chl	OH	Leu236  [A P2]	O	Leu236  [A P2]
-6.6	Chl	OH	Leu151 [A2]	O	Leu151  [A2]
-6.4	Chl	OH	Ile127 [B P1]	O	Ile127 [B P1]	Ile154 [B2]	Phe157 [B2]	Gly158 [B2]
-6.4	Chl	OH	Tyr42 [A1]	OH	Tyr42 [A1]	Phe148 [B2]	Tyr149 [B2]
Two-pore domain TRAAK in non-conductive down state in Tl+, human, 4wfh
-9.9	Chl	OH	Ile127 [B P1]	O	Ile154 [B2]	Gly158  [B2]
-8.5	Chl	OH	Thr237 [A P2]	O	Thr237 [A P2]	Thr238 [A P2]
	Chl	OH	Thr238 [A P2]	OG1
-8.3	Chl	OH	Leu236 [A P2]	O	Leu236 [A P2]	Thr237 [A P2]
-8	Chl	OH	Leu151 [A2]	O	Leu151 [A2]
-6.3	Chl	OH	Tyr42 [A1]	OH	Tyr42 [A1]	Phe148 [B2]	Tyr149 [B2]
-5.9	Chl	OH	Leu208 [B3]	O	Leu208 [B3]	Pro213 [B3]	Trp264 [B4]
Two-pore domain TRAAK in conductive up state in K+, human, 4wfe
6.5	Chl	OH	Tyr42  [B1]	OH	Phe148 [A2]	Tyr149 [A2]	Tyr42 [B1]
-6.1	Chl	OH	Tyr271 [A4]	OH	Cys206 [A3]	Tyr271 [A4]
	Tyr271 [A4]	OH	Chl	OH
Two-pore domain TRAAK in conductive up state in Tl+, human, 4wfg
-6.6	Tyr42 [A1]	OH	Chl	OH	Tyr42 [A1]	Phe148 [B2]	Tyr149 [B2]
-6.3	Chl	OH	Tyr42 [A1]	OH	Tyr42 [A1]	Phe148 [B2]	Tyr149 [B2]
	Tyr42 [A1]	OH	Chl	OH
Two-pore domain TRAAK, domain-swapped, closed fenestrations, human, 4i9w
-6.8	Chl	OH	Tyr42 [A1]	OH	Tyr42  [A1]	Phe148 [B2]	Tyr149 [B2]
Two-pore domain TREK-1 up state human, 4twk
-7.5	Chl	OH	Tyr284 [A4]	OH	Ile215 [A3]	Tyr284 [A4]
-6.1	Chl	OH	Tyr57 [B1]	OH	Ile161 [A2]	Tyr162 [A2]	Leu165 [A2]	Tyr57 [B1]
Two-pore domain TREK-1 up state mouse, 5vk5
-6.2	Chl	OH	Tyr57 [A1]	OH	Tyr57 [A1]	Ile161 [B2]	Tyr162 [B2]
-5.9	Chl	OH	Leu221 [A3]	O	Leu221 [A3]	Pro226 [A1]	Trp277 [A4]
Two-pore domain TREK-1 up state mouse, 5vkn
-5.6	Chl	OH	Tyr284 [A4]	OH	Cys219 [A3]	Tyr284 [A4]
-5.5	Chl	OH	Leu221 [A3]	O	Leu221 [A3]	Phe222 [A3]
Two-pore domain TREK-1 complex with ML402, mouse, 5vkp
-5.6	Chl	OH	Leu221 [A3]	O	Leu221 [A3]	Trp277 [A4]
Two-pore domain TREK-2 up state human, 4bw5
-6.6	Chl	OH	Tyr87 [A1]	OH	Tyr87 [A1]	Leu191 [B2]	Tyr192 [B2]	Tyr87 [B1]
Two-pore domain TREK-2 down state human (res. 3.8 A), 4xdj
-8.1	Chl	OH	Thr281 [A P2]	OG1	Thr280 [A P2]	Thr281 [A P2]
-7.8	Chl	OH	Ile194 [A2]	O	Ile194 [A2]
-7.6	Chl	OH	Leu279 [B P2]	O	Leu279 [B P2]
Two-pore domain TREK-2 down state, Br-fluoxetine bound, human, 4xdl
-8.2	Chl	OH	Ile194 [C2]	O	Ile194 [C2]
-8.2	Chl	OH	Thr281 [D P2]	OG1	Thr280 [D P2]	Thr281 [D P2]
Two-pore domain TREK-2 down state, norfluoxetine bound (res 3.6 Å), human, 4xdk
-8.4	Chl	OH	Ile170 [A P1]	O	Ile197 [A2]	Gly201 [A2]
-8.2	Chl	OH	Leu279 [B P2]	O	Leu279 [B P2]	Thr280 [B P2]	Thr281 [B P2]
Voltage-gated channel Kv1.2, rat, 3lut
None
Voltage-gated channel Kv1.2, rat, 2a79
-8.0	Chl	OH	Thr401 [A6]	OG1	Phe334 [A5]	Thr401 [A6]
-7.9	Chl	OH	Thr401 [A6]	OG1	Ala397 [A5]	Thr401 [A6]
Voltage-gated channel Kv1.2/Kv2.1 paddle chimera [PDB numbering changed to match 2a79], rat, 2r9r
-6.3	Chl	OH	Thr401 [A6]	OG1	Phe334 [A5]	Gly338 [A5]	Thr401 [A6]
Voltage-gated channel Kv1.2/Kv2.1 paddle chimera [PDB numbering changed to match 2a79] rat, 3lnm
-7.8	Chl	OH	Thr401 [A6]	OG1	Phe334 [A5]	Gly338 [A5]	Met372 [A P]	Thr401 [A6]
Voltage-gated channel Kv1.2/Kv2.1 paddle chimera, inactivated V410W mutant, rat, 5wie
None
Inward-rectifier Kir 2.2 chicken, 3jyc
-6.7	Trp94 [A1]	NE1	Chl	O	Trp94 [A1]	Gln141 [A P]
Inward-rectifier Kir 2.2 mutant apo form, 3spj
-9.1	Chl	OH	Gln141 [A P]	O	Gln141 [A P]	Ser166 [A2]	Gly169 [A2]	Cys170 [A2]
-7.7	Trp94 [A1]	NE1	Chl	O	Phe90 [A1]	Trp94 [A1]	Gln141 [A P]
Inward-rectifier Kir 2.2 in complex with PIP2 chicken, 3spi
-7.0	Chl	OH	Gln141 [A P]	O	Gln141 [A P]	Ser166 [A2]	Gly169 [A2]	Cys170 [A2]
Inward-rectifier Kir 2.2 mutant in complex with PIP2 chicken, 3spg
None
Inward-rectifier Kir 2.2 mutant in complex with PIP2 chicken, 3sph
None
Inward-rectifier Kir 2.2 in complex with PPA chicken, 3spc
None
Inward-rectifier Kir 2.2 K62W mutant chicken, 5kuk
None
G-protein gated channel, GIRK2 (Kir 3.2) wild type. mouse, 3syo
-7.0	Chl	OH	Ser181 [A2]	OG	Ser177 [A2]	Gly180 [A2]	Ser181 [A2]
G-protein gated channel, GIRK2 (Kir 3.2) D228N mutant. mouse, 3syc
-6.1	Chl	OH	Tyr102 [A1]	OH	Tyr102 [A1]
	Tyr102 [A1]	OH	Chl	OH
-6.0	Chl	OH	Glu152 [B P]	OE2	Tyr102 [B1]	Glu152 [B P]
	Tyr102 [B1]	OH	Chl	OH
G-protein gated channel, GIRK2 (Kir 3.2) wild type plus PIP2, mouse, 3sya
-7.2	Chl	OH	Ser181 [A2]	OG	Ser177 [A2]	Ser181 [A2]	Tyr102 [D1]
G-protein gated channel, GIRK2 (Kir 3.2) R201A mutant plus PIP2, mouse, 3syq
-9.1	Chl	OH	Ser181 [C2]	OG	Ser177 [C2]	Ser181 [C2]
-9.1	Chl	OH	Glu152 [B P]	O	Glu152 [B P]	Gly180 [B2]
	Chl	OH	Gly180 [B2]	O
-7.9	Chl	OH	Ser177 [B2]	O	Ser177 [B2]	Gly180 [B2]	Ser181 [B2]
	Chl	OH	Ser181 [B2]	OG
-7.5	Chl	OH	Tyr102 [D1]	OH	Tyr102 [D1]	Asn184 [D2]
	Tyr102 [D1]	OH	Chl	OH
G-protein gated channel, GIRK2 (Kir 3.2) plus G-protein subunits. mouse, 4kfm
-9.6	Chl	OH	Ser181 [F2]	OG	Ser177  [F2]	Ser181  [F2]
-8.9	Chl	OH	Glu152 [J P]	O	Glu152 [J P]	Gly180 [J2]
	Chl	OH	Glu152 [J P]	OE2
-8.5	Chl	OH	Ser181 [A2]	OG	Ser181  [A2]	Asn184 [J2]
Calcium-activated channel Slo1 (BK) sea slug, 5tj6
-7.5	Chl	OH	Ser29 [A1]	OG	Thr26 [A1]	Ser29 [A1]	Gly30 [A1]
Lysosomal K+-selective channel TMEM175 homolog, marine worm, 5vre
None
Calcium-ion selective Channels
Orai calcium release-activated CRAC channel, Drosophila, 4hkr
-6.8	Chl	OH	Thr283 [A4]	O	Thr283 [A4]	Leu286 [A4]	Ile287 [A4]
Orai calcium release-activated CRAC channel mutant, Drosophila, 4hks
-6.6	Chl	OH	Thr283 [A4]	O	Thr283 [A4]	Leu286 [A4]	Ile287 [A4]
Transient Receptor Potential (TRP) Channels
TRPM4 cation channel, apo state, human, 6bcj
None
TRPM4 cation channel, apo state, human, 6bcl
None
TRPM4 cation channel, ATP bound, human, 6bco
None
TRPM4 cation channel, ATP bound, human, 6bcq
None
TRPM4 cation channel, Ca-free, human, 6bqr
None
TRPM4 cation channel, Ca-bound, human, 6bqv
None
TRPML1,  human, 5wj9
-7.8	Chl	OH	Tyr439 [A5]	OH	Tyr439 [A5]	Ser500 [A6]
-6.9	Chl	OH	Ser503 [A6]	OG	Tyr499 [A6]	Ser503 [A6]
TRPML3,  marmoset, 5w3s
-7.1	Chl	OH	Tyr491 [A6]	OH	Tyr491 [A6]	Ile455 [D P]
	Tyr491 [A6]	OH	Chl	OH
TRPV1 rat, 3j5p
-7.7	Chl	OH	Thr550 [A4]	OG1	Met547 [A4]	Thr550 [A4]	Asn551 [A4]
-7.5	Chl	OH	Ser483 [A2]	OG	Ser483 [A2]	Gly484 [A2]
	Ser483 [A2]	OG	Chl	OH
TRPV1 rat, 5irz
-8.2	Chl	OH	Ser483 [A2]	OG	Ser483 [A2]	Gly484 [A2]
	Ser483 [A2]	OG	Chl	OH
-8.0	Chl	OH	Thr550 [A4]	OG1	Ala546 [A4]	Met547 [A4]	Thr550 [A4]
TRPV1 complex with DkTx and RTX, rat, 5irx
-8.6	Chl	OH	Thr550 [A4]	OG1	Ala546 [A4]	Met547 [A4]	Thr550 [A4]
-6.9	Chl	OH	Ser483 [A2]	OG	Ser483 [A2]	Gly484 [A2]
	Ser483 [A2]	OG	Chl	OH	Ser483 [A2]	Gly484 [A2]
TRPV1 complex with capsaicin, rat, 5is0
-8.7	Chl	OH	Thr550 [A4]	OG1	Ala546 [A4]	Met547 [A4]	Thr550 [A4]
-6.6	Chl	OH	Ser483 [A2]	OG	Ile479 [A2]	Val482 [A2]	Ser483 [A2]
TRPV6 rat, 5iwk
None
TRPV6 rat, 5wo6
-5.8	Chl	OH	Thr430 [A3]	OG1	Val426 [A3]	Ile427 [A3]	Thr430 [A3]
TRPV6 rat, 5wo7
-6.3	Chl	OH	Val498 [A5]	O	Val498 [A5]	Val499 [A5]	Gly502 [A5]
TRPV6-Del1, rat, 5wo8
-6.1	Chl	OH	Thr430 [A3]	OG1	Val426 [A3]	Ile427 [A3]	Thr430 [A3]
TRPV6, plus Ca2+, rat, 5wo9
-7.1	Chl	OH	Cys462 [A4]	O	Trp461 [A4]	Cys462 [A4]	Val464 [A4]	Met465 [A4]
	Met465 [A4]	N	Chl	OH
PKD2 polycystic kidney disease channel, human, 5t4d
-6.7	Chl	OH	Thr663 [A6]	OG1	Tyr611 [A5]	Thr663 [A6]
	Tyr611 [A5]	OH	Chl	OH
Glutamate Receptors
GluA2 glutamate receptor (AMPA) apo form A, rat, 4u2p
-9.1	Tyr533 [A1]	OH	Chl	OH	Tyr533 [A1]	Arg599 [D2]
-8.2	Chl	OH	Thr609 [A2]	OG1	Trp605 [A2]	Thr609 [A2]
-7.3	Chl	OH	Thr609 [A2]	OG1	Trp605 [A2]	Thr609 [A2]
	Trp605 [A2]	NE1	Chl	OH
GluA2 glutamate receptor (AMPA) with kainate crystal form A, rat, 4u1w
-7.8	Chl	OH	Thr609 [A2]	OG1	Trp605 [A2]	Thr609 [A2]
-7.5	Trp605 [A2]	NE1	Chl	OH	Trp605 [A2]	Thr609 [A2]
GluA2 glutamate receptor (AMPA) with kainate crystal form B, rat, 4u1x
-7.6	Chl	OH	Thr609 [A2]	OG1	Thr609 [A2]
-6.8	Chl	OH	Thr609 [A2]	OG1	Thr609 [A2]	Trp606 [D2]
GluA2 glutamate receptor (AMPA) mutant with toxin etc, rat, 4u5b
-9.2	Tyr533 [C1]	OH	Chl	OH	Arg599 [B2]	Tyr533 [C1]
-8.3	Chl	OH	Thr609 [A2]	OG1	Trp605 [A2]	Thr609 [A2]
	Trp605 [A2]	NE1	Chl	OH
-7.7	Trp605 [A2]	NE1	Chl	OH	Trp605 [A2]
P2X channels
ATP-gated P2X3 channel closed apo state, human, 5svj
-6.9	Chl	OH	Thr336 [A2]	OG1	Gly333 [A2]	Thr336 [A2]
ATP-gated P2X3 channel ATP bound open state, human, 5svk
-7.7	Chl	OH	Ser331[A2]	OG	Thr330 [A2]	Ser331 [A2]
	Chl	OH	Thr330 [A2]	OG1
	Chl	OH	Thr330 [A2]	O
-6.2	Chl	OH	Ser36 [A1]	OG1	Leu33 [A1]	Ser36 [A1]	Tyr37 [A1]
ATP-gated P2X3 channel ATP-bound, desensitized state, human, 5svl
-8.9	Chl	OH	Thr330 [A2]	OG1	Thr330 [A2]	Ser331 [A2]
-8.9	Chl	OH	Ser331 [A2]	OG	Thr330 [A2]	Ser331 [A2]
ATP-gated P2X3 channel agonist bound desensitized state, human, 5svm
-11.4	Chl	OH	Ser331 [A2]	OG	Ala327 [A2]	Thr330 [A2]	Ser331 [A2]
	Chl	OH	Thr330 [A2]	OG1
ATP-gated P2X3 channel agonist bound desensitized state, human, 5svp
-11.4	Chl	OH	Ser331 [A2]	OG	Ala327 [A2]	Thr330 [A2]	Ser331 [A2]
	Chl	OH	Thr330 [A2]	OG1
ATP-gated P2X3 channel competitive antagonist bound closed  state, human, 5svq
None
ATP-gated P2X3 channel competitive antagonist bound  closed state, human, 5svr
-6.6	Chl	OH	Ser36 [A1]	OG	Ser36 [A1]
-6.3	Chl	OH	Thr336 [A2]	OG1	Val332 [A2]	Gly333 [A2]	Thr336 [A2]
ATP-gated P2X4 channel apo  state, zebra fish, 3h9v
None
ATP-gated P2X4 channel apo  closed state, zebra fish, 3i5d
None
ATP-gated P2X4 channel plus CTP open state, zebra fish, 5wzy
-6.9	Chl	OH	Ala344 [A2]	O	Ala344 [A2]	Ala347 [A2]	Leu348 [A2]
ATP-gated P2X4 channel ATP bound open  state, zebra fish, 4dw1
-7.3	Chl	OH	Gly343 [A2]	O	Gly343 [A2]	Ala344 [A2]
ATP-gated P2X4 channel ATP-free   closed state, zebra fish, 4dw0
None
ATP-gated P2X4 channel ATP bound open state, Gulf Coast tick, 5f1c
None
ATP-gated P2X7 channel plus competitive antagonist, chicken, 5xw6
-8.4	Chl	OH	Ser326 [B2]	OG	Thr322 [B2]	Ser326 [B2]
-6.6	Chl	OH	Tyr330 [C2]	OH	Tyr330 [C2]
-6.5	Chl	OH	Thr327 [C2]	OG1	Thr327 [C2]	Ile328 [C2]
	Thr327 [C2]	OG1	Chl	OH
Acid-sensing ion-channel (ASIC), chicken, 4nyk
None
Chloride channels
Bestrophin-1 (BEST1) Ca-activated Cl channel, jungle fowl, 4rdq
-9.5	Chl	OH	Ala73 [A2]	O	Asn70 [A2]	Ser71 [A2]	Ala73 [A2]	Glu74 [A2]
Bestrophin-1 (BEST1) Ca-activated Cl channel mutant, jungle fowl, 5t5n
-8.9	Chl	OH	Ala73 [A2]	O	Asn70 [A2]	Ala73 [A2]	Arg255 [A3]
Neurotransmitter-gated ion channels of the Cys-loop receptor family
Glycine receptor complex with strychnine, human, 5cfb
-7.2	Chl	OH	Ser296 [A3]	OG	Leu292 [A3]	Ser296 [A3]
Glycine receptor complex with AM-3607, human, 5tio
-7.5	Chl	OH	Ser296 [A3]	OG	Leu292 [A3]	Ser296 [A3]
Glycine receptor, mutant, complex with AM-3607, human, 5tin
-8.3	Chl	OH	Ser296 [A3]	OG	Leu292 [A3]	Phe293 [A3]	Ser296 [A3]
Glycine receptor, complex with Gly and  ivermectin, human, 5vdh
-8.0	Chl	OH	Ser296 [A3]	OG	Leu292 [A3]	Phe293 [A3]	Ser296 [A3]
GABA-A receptor (β3 homopentamer), human, 4cof
-7.5	Chl	OH	Ser436 [A4]	OG	Pro432 [A4]	Phe435 [A4]	Ser436 [A4]
GABA-A receptor (α5 TMD - β3 ECD chimera) with pregnanolone, human, 5o8f
-8.1	Chl	OH	Ser302 [A3]	OG	Ala298 [A3]	Ser302 [A3]
	Ser302 [A3]	OG	Chl	OH
-7.5	Chl	OH	Thr408 [A4]	OG1	Leu405 [A4]	Thr408 [A4]	Phe409 [A4]
Serotonin 5-HT3 receptor, mouse, 4pir
-7.6	Chl	OH	Thr445 [A4]	OG1	Ala441 [A4]	Tyr442 [A4]	Thr445 [A4]