Structure of PDB 8eio Chain A Binding Site BS07

Receptor Information

>8eio Chain A (length=1162) Species: 9606 (Homo sapiens)

MQRSPLEKASVVSKLFFSWTRPILRKGYRQRLELSDIYQIPSVDSADNLS
EKLEREWDRELASKKNPKLINALRRCFFWRFMFYGIFLYLGEVTKAVQPL
LLGRIIASYDPDNKEERSIAIYLGIGLCLLFIVRTLLLHPAIFGLHHIGM
QMRIAMFSLIYKKTLKLSSRVLDKISIGQLVSLLSNNLNKFDEGLALAHF
VWIAPLQVALLMGLIWELLQASAFCGLGFLIVLALFQAGLGRMMMKYRDQ
RAGKISERLVITSEMIENIQSVKAYCWEEAMEKMIENLRQTELKLTRKAA
YVRYFNSSAFFFSGFFVVFLSVLPYALIKGIILRKIFTTISFCIVLRMAV
TRQFPWAVQTWYDSLGAINKIQDFLQKQEYKTLEYNLTTTEVVMENVTAF
WEGTPVLKDINFKIERGQLLAVAGSTGAGKTSLLMVIMGELEPSEGKIKH
SGRISFCSQFSWIMPGTIKENIIGVSYDEYRYRSVIKACQLEEDISKFAE
KDNIVLGEGGITLSGGQRARISLARAVYKDADLYLLDSPFGYLDVLTEKE
IFESCVCKLMANKTRILVTSKMEHLKKADKILILHEGSSYFYGTFSELQN
LWNTYLRYITVHKSLIFVLIWCLVIFLAEVAASLVVLWLLGSYAVIITST
SSYYVFYIYVGVADTLLAMGFFRGLPLVHTLITVSKILHHKMLHSVLQAP
MSTLNTLKAGGILNRFSKDIAILDDLLPLTIFDFIQLLLIVIGAIAVVAV
LQPYIFVATVPVIVAFIMLRAYFLQTSQQLKQLESEGRSPIFTHLVTSLK
GLWTLRAFGRQPYFETLFHKALNLHTANWFLYLSTLRWFQMRIEMIFVIF
FIAVTFISILTTGEGEGRVGIILTLAMNIMSTLQWAVNSSIDVDSLMRSV
SRVFKFIDMPTEGIWPSGGQMTVKDLTAKYTEGGNAILENISFSISPGQR
VGLLGRTGSGKSTLLSAFLRLLNTEGEIQIDGVSWDSITLQQWRKAFGVI
PQKVFIFSGTFRKNLDPYEQWSDQEIWKVADEVGLRSVIEQFPGKLDFVL
VDGGCVLSHGHKQLMCLARSVLSKAKILLLDQPSAHLDPVTYQIIRRTLK
QAFADCTVILCEHRIEAMLECQQFLVIEENKVRQYDSIQKLLNERSLFRQ
AISPSDRVKLFP

Ligand information

• Ligand ID: WJX
• InChI: InChI=1S/C26H34F3N7O4S/c1-16-12-25(5,6)35(13-16)22-18(23(37)33-41(38,39)19-14-34(7)31-17(19)2)8-9-20(30-22)36-11-10-21(32-36)40-15-24(3,4)26(27,28)29/h8-11,14,16H,12-13,15H2,1-7H3,(H,33,37)/t16-/m0/s1
• InChIKey: MVRHVFSOIWFBTE-INIZCTEOSA-N
• SMILES:
  CACTVS 3.385: C[CH]1CN(c2nc(ccc2C(=O)N[S](=O)(=O)c3cn(C)nc3C)n4ccc(OCC(C)(C)C(F)(F)F)n4)C(C)(C)C1
  CACTVS 3.385: C[C@@H]1CN(c2nc(ccc2C(=O)N[S](=O)(=O)c3cn(C)nc3C)n4ccc(OCC(C)(C)C(F)(F)F)n4)C(C)(C)C1
  OpenEye OEToolkits 2.0.7: Cc1c(cn(n1)C)S(=O)(=O)NC(=O)c2ccc(nc2N3C[C@H](CC3(C)C)C)n4ccc(n4)OCC(C)(C)C(F)(F)F
  OpenEye OEToolkits 2.0.7: Cc1c(cn(n1)C)S(=O)(=O)NC(=O)c2ccc(nc2N3CC(CC3(C)C)C)n4ccc(n4)OCC(C)(C)C(F)(F)F
  ACDLabs 12.01: O=S(=O)(NC(=O)c1ccc(nc1N1CC(C)CC1(C)C)n1ccc(OCC(C)(C)C(F)(F)F)n1)c1cn(C)nc1C
• Formula: C26 H34 F3 N7 O4 S
• Name: (6P)-N-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-6-[3-(3,3,3-trifluoro-2,2-dimethylpropoxy)-1H-pyrazol-1-yl]-2-[(4S)-2,2,4-trimethylpyrrolidin-1-yl]pyridine-3-carboxamide;
  Elexacaftor
• ChEMBL: CHEMBL4298128
• DrugBank: DB15444
• PDB chain: 8eio Chain A Residue 1508

Receptor-Ligand Complex Structure

Structure summary

• PDB: 8eio Molecular structures reveal synergistic rescue of Delta 508 CFTR by Trikafta modulators.
• Resolution: 2.8 Å
• Binding residue (original residue number in PDB): R21 L24 I132 W1098 R1102 M1105 V1108 I1109
• Binding residue (residue number reindexed from 1): R21 L24 I132 W838 R842 M845 V848 I849
• Annotation score: 1

Enzymatic activity

• Enzyme Commision number: 5.6.1.6: channel-conductance-controlling ATPase.

Gene Ontology

Molecular Function

• GO:0005254 chloride channel activity
• GO:0005260 intracellularly ATP-gated chloride channel activity
• GO:0005515 protein binding
• GO:0005524 ATP binding
• GO:0015106 bicarbonate transmembrane transporter activity
• GO:0015108 chloride transmembrane transporter activity
• GO:0016853 isomerase activity
• GO:0016887 ATP hydrolysis activity
• GO:0017081 chloride channel regulator activity
• GO:0019869 chloride channel inhibitor activity
• GO:0019899 enzyme binding
• GO:0030165 PDZ domain binding
• GO:0042626 ATPase-coupled transmembrane transporter activity
• GO:0043225 ATPase-coupled inorganic anion transmembrane transporter activity
• GO:0051087 protein-folding chaperone binding
• GO:0071889 14-3-3 protein binding
• GO:0106138 Sec61 translocon complex binding
• GO:0140359 ABC-type transporter activity

Biological Process

• GO:0006695 cholesterol biosynthetic process
• GO:0006811 monoatomic ion transport
• GO:0006821 chloride transport
• GO:0006904 vesicle docking involved in exocytosis
• GO:0015701 bicarbonate transport
• GO:0030301 cholesterol transport
• GO:0034220 monoatomic ion transmembrane transport
• GO:0034976 response to endoplasmic reticulum stress
• GO:0035377 transepithelial water transport
• GO:0035774 positive regulation of insulin secretion involved in cellular response to glucose stimulus
• GO:0045921 positive regulation of exocytosis
• GO:0048240 sperm capacitation
• GO:0050891 multicellular organismal-level water homeostasis
• GO:0051454 intracellular pH elevation
• GO:0051649 establishment of localization in cell
• GO:0055085 transmembrane transport
• GO:0060081 membrane hyperpolarization
• GO:0070175 positive regulation of enamel mineralization
• GO:0071320 cellular response to cAMP
• GO:0097186 amelogenesis
• GO:1902161 positive regulation of cyclic nucleotide-gated ion channel activity
• GO:1902476 chloride transmembrane transport
• GO:1902943 positive regulation of voltage-gated chloride channel activity
• GO:1904322 cellular response to forskolin

Cellular Component

• GO:0005634 nucleus
• GO:0005737 cytoplasm
• GO:0005765 lysosomal membrane
• GO:0005768 endosome
• GO:0005769 early endosome
• GO:0005783 endoplasmic reticulum
• GO:0005789 endoplasmic reticulum membrane
• GO:0005829 cytosol
• GO:0005886 plasma membrane
• GO:0009986 cell surface
• GO:0010008 endosome membrane
• GO:0016020 membrane
• GO:0016324 apical plasma membrane
• GO:0030660 Golgi-associated vesicle membrane
• GO:0030669 clathrin-coated endocytic vesicle membrane
• GO:0031901 early endosome membrane
• GO:0032991 protein-containing complex
• GO:0034707 chloride channel complex
• GO:0055037 recycling endosome
• GO:0055038 recycling endosome membrane

External links

• PDB: RCSB:8eio, PDBe:8eio, PDBj:8eio
• PDBsum: 8eio
• PubMed: 36264792
• UniProt: P13569|CFTR_HUMAN Cystic fibrosis transmembrane conductance regulator (Gene Name=CFTR)