Product Description: non-SERCA-type Ca2+ -transporting P-ATPase
SignalP Peptide: N/A
# Transmembrane Domains: 8
EC Numbers: 3.6.3.2 (Transferred entry: 7.2.2.14);3.6.3.8 (Transferred entry: 7.2.2.10)
Curated GO (PlasmoDB):
| Type | GO Term | Name |
|---|---|---|
| Function | GO:0016887 | ATP hydrolysis activity |
| Function | GO:0005388 | P-type calcium transporter activity |
| Function | GO:0008553 | P-type proton-exporting transporter activity |
| Process | GO:0070588 | calcium ion transmembrane transport |
| Process | GO:0006874 | cellular calcium ion homeostasis |
| Process | GO:0002028 | regulation of sodium ion transport |
| Process | GO:0009410 | response to xenobiotic stimulus |
Expression by stage (LR - Le Roch et al., and MCA - Malaria Cell Atlas):
| Stage | LR class | MCA mean | MCA prop. zeros |
|---|---|---|---|
| Sporozoite | expressed | N/A | N/A |
| Ring | expressed | 0.63 | 0.70 |
| Trophozoite | expressed | 0.86 | 0.54 |
| Schizont | expressed | 0.88 | 0.57 |
| Gametocyte | expressed | 0.45 | 0.75 |
More info:
Old (Pf3D7v3) Gene ID: PF3D7_1211900
Resistome Missense Mutations: A184S, A187V, I203M, I203L, A211T, I263V, L350H, G358S, I398F, P412T, V415D, G933A, P966T, P966S, P990R
Resistome Compounds with Missense Mutations: Cipargamin/KAE609/NITD609, GNF-Pf4492/NITD358, KAE678/NITD678, SJ247, SJ279, SJ311, SJ733
Resistome # Samples with Disruptive Mutations: 20 (20 missense, 16 "interesting" missense)
Zhang Phenotype: Non - Mutable in CDS
MIS: 0.119 | MFS: -3.089 | #Insertions: 0
PlasmoGEM Phenotype: Slow (Pb ortholog: PBANKA_0610400)
RMgmDB ABS Phenotype: Different from wild type (Pb ortholog: PBANKA_0610400)
Modification: Disrupted | RMgm-2097
More info: PhenoPlasm Link
AlphaFill Uniprot ID: A0A143ZZK9
"Best" AlphaFill ligand hit: PCW ((z,z)-4-hydroxy-n,n,n-trimethyl-10-oxo-7-[(1-oxo-9-octadecenyl)oxy]-3,5,9-trioxa-4-phosphaheptacos-18-en-1-aminium-4-oxide, Local RMSD=0.02) with 5XA8 (Global RMSD=5.97)
BRENDA EC Inhibitors:
Orthology to BindingDB Entries:
| UniProt | Protein Name | Species | Homology Source | BindingDB Ligands |
|---|---|---|---|---|
| O14983 | Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 | Homo sapiens | OrthoDB | CHEMBL191927CHEMBL362947CHEMBL191633CHEMBL365703... |
| P04191 | Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 | Oryctolagus cuniculus | OrthoDB | hydroquinone derivative, 2bhydroquinone derivative, 2chydroquinone derivative, 3ahydroquinone derivative, 5a... |
| Q64541 | Sodium/potassium-transporting ATPase subunit alpha-4/beta-1 | OrthoDB | CHEMBL4095996CHEMBL4087192CHEMBL4072996CHEMBL4059538... | |
| Q64518 | Sarcoplasmic/endoplasmic reticulum calcium ATPase 3 | OrthoDB | 4-NONYLPHENOL | |
| P11507 | Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 | OrthoDB | ABAMECTINBisphenol A (BPA) | |
| O55143 | Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 | OrthoDB | 4-NONYLPHENOL | |
| P05023 | Sodium/potassium-transporting ATPase subunit alpha-1 | OrthoDB | cid_439501DigoxigeninMLS000069819DOH (1)... | |
| P54707 | Potassium-transporting ATPase alpha chain 2 | Homo sapiens | OrthoDB | CHEMBL318786DigitoxigeninCHEMBL104027CHEMBL323301... |
| P50997 | Sodium/potassium-transporting ATPase subunit alpha-1 | Canis familiaris | OrthoDB | CHEMBL2068940MLS000069787DigitoxigeninMLS000069819... |
| P16615 | Sarcoplasmic/endoplasmic reticulum calcium ATPase 2 | OrthoDB | CHEBI:3962CHEMBL4534285CHEBI:17734CHEMBL4207081... | |
| P06685 | Sodium/potassium-transporting ATPase subunit alpha-1/beta-1 | Rattus | OrthoDB | ABAMECTINcid_439501 |
| Q93084 | Sarcoplasmic/endoplasmic reticulum calcium ATPase 3 | OrthoDB | CAS# 88-58-4CHEBI:17734MLS000028812CHEMBL4534285... | |
| P19156 | Potassium-transporting ATPase alpha chain 1/subunit beta | OrthoDB | US9114126, MB7US10308605, Example 7US10308605, Example 11US10308605, Example 12... | |
| P20648 | Potassium-transporting ATPase alpha chain 1/subunit beta | Homo sapiens | OrthoDB | CHEMBL153567CHEMBL20364CHEMBL20372CHEMBL282218... |
| P05024 | Sodium/potassium-transporting ATPase subunit alpha-1 | Sus scrofa | OrthoDB | CHEMBL178993Uscharin derivativeUscharin derivativeCHEMBL175806 |
| P50993 | Sodium/potassium-transporting ATPase subunit alpha-2/beta-1 | OrthoDB | cid_439501DigoxigeninMLS000069819DOH (1)... |
Ortholog Group (OrthoMCL): OG6_100158
Most Similar Human Ortholog: H0YAH2
TM-align score: 0.83 | RMSD: 1.32
Seq Identity: 0.39 | Length: 49 / 1264
All Human Orthologs (OrthoMCL):
| Gene ID | Description |
|---|---|
| ENSG00000017260 | ATPase secretory pathway Ca2+ transporting 1 |
| ENSG00000064270 | ATPase secretory pathway Ca2+ transporting 2 |
| ENSG00000074370 | ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 3 |
| ENSG00000174437 | ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 2 |
| ENSG00000196296 | ATPase sarcoplasmic/endoplasmic reticulum Ca2+ transporting 1 |
Protein Length: 1264 | Molecular Weight (kDa): 140.262
UniProt ID(s): A0A024A091, A0A143ZZK9, E1CC02, E1CC10, E5RU00, Q27721, Q27724, Q5R2K7, Q9U445
PDB ID(s): None
Isoelectric Point: 5.75
Protein Domain Annotations:
| Source | Family ID | Description |
|---|---|---|
| InterPro | IPR001757 | P-type ATPase |
| InterPro | IPR004014 | Cation-transporting P-type ATPase, N-terminal |
| InterPro | IPR006068 | Cation-transporting P-type ATPase, C-terminal |
| InterPro | IPR008250 | P-type ATPase, A domain superfamily |
| InterPro | IPR018303 | P-type ATPase, phosphorylation site |
| InterPro | IPR023298 | P-type ATPase, transmembrane domain superfamily |
| InterPro | IPR023299 | P-type ATPase, cytoplasmic domain N |
| InterPro | IPR036412 | HAD-like superfamily |
| PFam | PF00122 | Cation-transporting P-type ATPase, C-terminal |
| PFam | PF00689 | Cation-transporting P-type ATPase, N-terminal |
| PFam | PF00690 | |
| PFam | PF00702 | |
| PFam | PF13246 | |
| Superfamily | SSF56784 | HAD-like superfamily |
| Superfamily | SSF81653 | P-type ATPase, A domain superfamily |
| Superfamily | SSF81660 | P-type ATPase, cytoplasmic domain N |
| Superfamily | SSF81665 | P-type ATPase, transmembrane domain superfamily |
MalariaGEN Pf7 (worldwide samples) # unique SNV/indels:
Homozygous genotype calls only
| variant type | common | rare | doubleton | singleton |
|---|---|---|---|---|
| synonymous | 9 | 62 | 21 | 82 |
| disruptive | 28 | 81 | 47 | 87 |
| missense | 28 | 81 | 44 | 72 |
Any inclusion in genotype call
| variant type | common | rare | doubleton | singleton |
|---|---|---|---|---|
| synonymous | 20 | 131 | 59 | 90 |
| disruptive | 42 | 154 | 89 | 180 |
| missense | 39 | 138 | 75 | 144 |
PlasmoDB Total SNPs: 190
Non-coding: 138 | Synonymous: 21 | Nonsynonymous: 31 | Stop Codon: 0
| PMID | Title | Authors | DOI/Link |
|---|---|---|---|
| 12368864 | Genome sequence of the human malaria parasite Plasmodium falciparum. | Gardner MJ, Hall N, ..., Barrell B | 10.1038/nature01097 |
| 16267556 | A protein interaction network of the malaria parasite Plasmodium falciparum. | LaCount DJ, Vignali M, ..., Hughes RE | 10.1038/nature04104 |
| 23414762 | Na(+) regulation in the malaria parasite Plasmodium falciparum involves thecation ATPase PfATP4 and is a target of the spiroindolone antimalarials. | Spillman NJ, Allen RJ, ..., Kirk K | 10.1016/j.chom.2012.12.006 |
| 25322084 | Mutations in the P-type cation-transporter ATPase 4, PfATP4, mediate resistanceto both aminopyrazole and spiroindolone antimalarials. | Flannery EL, McNamara CW, ..., Winzeler EA | 10.1021/cb500616x |
| 35598441 | Combining SJ733, an oral ATP4 inhibitor of Plasmodium falciparum, with thepharmacokinetic enhancer cobicistat: An innovative approach in antimalarial drugdevelopment | Gaur AH, Panetta JC, ..., Guy RK | 10.1016/j.ebiom.2022.104065 |
| 34930267 | Hepatic safety and tolerability of cipargamin (KAE609), in adult patients withPlasmodium falciparum malaria: a randomized, phase II, controlled,dose-escalation trial in sub-Saharan Africa | Ndayisaba G, Yeka A, ..., Hughes D | 10.1186/s12936-021-04009-1 |
| 36190127 | Cation ATPase (ATP4) Orthologue Replacement in the Malaria Parasite Plasmodiumknowlesi Reveals Species-Specific Responses to ATP4-Targeting Drugs | Mohring F, van Schalkwyk DA, ..., Moon RW | 10.1128/mbio.01178-22 |
| 36411573 | Antimalarials Targeting the Malaria Parasite Cation ATPase P. falciparum ATP4(PfATP4) | Zagorska A, Jaromin A | 10.2174/1568026623666221121154354 |
| 36180431 | A G358S mutation in the Plasmodium falciparum Na(+) pump PfATP4 confersclinically-relevant resistance to cipargamin | Qiu D, Pei JV, ..., Lehane AM | 10.1038/s41467-022-33403-9 |
| 36409128 | Spirofused Tetrahydroisoquinoline-Oxindole Hybrids (Spiroquindolones) asPotential Multitarget Antimalarial Agents: Preliminary Hit Optimization andEfficacy Evaluation in Mice | Efange NM, Lobe MMM, ..., Efange SMN | 10.1128/aac.00607-22 |