8K8E: Human gamma-secretase
Human gamma-secretase in complex with a substrate mimetic. Determined by electron microscopy at 2.6 Å resolution. Released 31 Jan 2024.
- Method
- Electron microscopy
- Resolution
- 2.6 Å
- Organisms
- Homo sapiens, synthetic construct
- Chains
- 5
- Atoms
- 10,716
- Mol. weight
- 178.32 kDa
- Ligands
- NAG, PC1, CLR
- Released
- 31 Jan 2024
Explore 8K8E in 3D
Show helices and sheets
RCSB PDB
PDBe
Secondary structure: helices and β-sheets
8K8E contains 70 α-helices and 36 β-strands across 5 chains. Residue ranges use author residue numbering, as in the PDB file, from PDBe. To see them in 3D, choose the Cartoon representation with Secondary structure coloring: helices, sheets and coils get different colors.
Chain A: 37 helices, 31 β-strands
| Element | Residues | Length | Sheet |
|---|
| α-helix | 37-39 | 3 | |
| β-strand | 42-44 | 3 | 1 |
| β-strand | 47-49 | 3 | 1 |
| β-strand | 53-54 | 2 | 2 |
| β-strand | 59-60 | 2 | 2 |
| β-strand | 61 | 1 | 3 |
| β-strand | 69-76 | 8 | 1 |
| α-helix | 80-86 | 7 | |
| β-strand | 94-99 | 6 | 1 |
| α-helix | 100-102 | 3 | |
| α-helix | 105-112 | 8 | |
| α-helix | 115-117 | 3 | |
| β-strand | 118-124 | 7 | 1 |
| α-helix | 125-126 | 2 | |
| β-strand | 135 | 1 | 4 |
| α-helix | 143-145 | 3 | |
| α-helix | 154-156 | 3 | |
| β-strand | 168 | 1 | 4 |
| α-helix | 171-173 | 3 | |
| β-strand | 175 | 1 | 3 |
| β-strand | 180-183 | 4 | 1 |
| α-helix | 186-195 | 10 | |
| α-helix | 196-200 | 5 | |
| α-helix | 201-202 | 2 | |
| α-helix | 203-205 | 3 | |
| α-helix | 206-209 | 4 | |
| β-strand | 212-218 | 7 | 1 |
| β-strand | 221-222 | 2 | 5 |
| α-helix | 227-236 | 10 | |
| β-strand | 250 | 1 | 2 |
| β-strand | 253-259 | 7 | 6 |
| α-helix | 268-270 | 3 | |
| β-strand | 275-281 | 7 | 6 |
| α-helix | 295-299 | 5 | |
| α-helix | 300-313 | 14 | |
| β-strand | 324-330 | 7 | 6 |
| α-helix | 338-349 | 12 | |
| α-helix | 356-358 | 3 | |
| β-strand | 359-365 | 7 | 6 |
| β-strand | 375-379 | 5 | 6 |
| α-helix | 384-386 | 3 | |
| α-helix | 388-405 | 18 | |
| β-strand | 412-414 | 3 | 6 |
| α-helix | 422-423 | 2 | |
| α-helix | 427-431 | 5 | |
| β-strand | 437-442 | 6 | 6 |
| α-helix | 460-463 | 4 | |
| α-helix | 475-478 | 4 | |
| α-helix | 482-502 | 21 | |
| α-helix | 515-526 | 12 | |
| α-helix | 532-535 | 4 | |
| α-helix | 541-545 | 5 | |
| α-helix | 562-575 | 14 | |
| β-strand | 577-579 | 3 | 7 |
| α-helix | 583-587 | 5 | |
| β-strand | 601-605 | 5 | 7 |
| α-helix | 608 | 1 | |
| β-strand | 609 | 1 | 8 |
| α-helix | 610 | 1 | |
| β-strand | 616 | 1 | 8 |
| β-strand | 619-623 | 5 | 7 |
| β-strand | 626-630 | 5 | 6 |
| α-helix | 633-635 | 3 | |
| β-strand | 649-650 | 2 | 2 |
| β-strand | 652-653 | 2 | 5 |
| β-strand | 657-663 | 7 | 1 |
| α-helix | 666-692 | 27 | |
| α-helix | 694-697 | 4 | |
Chain B: 16 helices, 3 β-strands
| Element | Residues | Length | Sheet |
|---|
| α-helix | 79-103 | 25 | |
| α-helix | 125-153 | 29 | |
| α-helix | 161-172 | 12 | |
| α-helix | 173-177 | 5 | |
| α-helix | 178-188 | 11 | |
| β-strand | 193-194 | 2 | 9 |
| α-helix | 195-214 | 20 | |
| α-helix | 219-239 | 21 | |
| α-helix | 243-262 | 20 | |
| α-helix | 269-272 | 4 | |
| α-helix | 274-277 | 4 | |
| α-helix | 284-286 | 3 | |
| β-strand | 287-288 | 2 | 10 |
| β-strand | 381-382 | 2 | 10 |
| α-helix | 383-398 | 16 | |
| α-helix | 404-428 | 25 | |
| α-helix | 435-448 | 14 | |
| α-helix | 449-453 | 5 | |
| α-helix | 454-462 | 9 | |
Chain C: 11 helices, 1 β-strand
| Element | Residues | Length | Sheet |
|---|
| α-helix | 3-20 | 18 | |
| α-helix | 21-25 | 5 | |
| α-helix | 29-60 | 32 | |
| α-helix | 65-103 | 39 | |
| α-helix | 114-139 | 26 | |
| α-helix | 140-142 | 3 | |
| β-strand | 146 | 1 | 1 |
| α-helix | 156-183 | 28 | |
| α-helix | 187-203 | 17 | |
| α-helix | 204-206 | 3 | |
| α-helix | 210-231 | 22 | |
| α-helix | 236-243 | 8 | |
Chain D: 4 helices, 1 β-strand
| Element | Residues | Length | Sheet |
|---|
| α-helix | 8-21 | 14 | |
| α-helix | 27-42 | 16 | |
| α-helix | 52-84 | 33 | |
| α-helix | 87-91 | 5 | |
| β-strand | 93-95 | 3 | 9 |
Chain H: 2 helices, 0 β-strands
| Element | Residues | Length | Sheet |
|---|
| α-helix | 2-5 | 4 | |
| α-helix | 10-12 | 3 | |
Molecules and chains
| Molecule | Chains | Type | Length | Organism | UniProt |
|---|
| Nicastrin | A | protein | 709 | Homo sapiens | Q92542 (AlphaFold model) |
| Presenilin-1 | B | protein | 467 | Homo sapiens | P49768 (AlphaFold model) |
| Gamma-secretase subunit APH-1A | C | protein | 265 | Homo sapiens | Q96BI3 (AlphaFold model) |
| Gamma-secretase subunit PEN-2 | D | protein | 101 | Homo sapiens | Q9NZ42 (AlphaFold model) |
| Zqn-gly-aib-val-val-ile-aib-phe-val-aib-gly-gly-gly-val-juu-leu-val-NH2 | H | protein | 18 | synthetic construct | |
Sequence of entity 1 (A), FASTA
>8K8E_1 Nicastrin (chains A)
MATAGGGSGADPGSRGLLRLLSFCVLLAGLCRGNSVERKIYIPLNKTAPCVRLLNATHQI
GCQSSISGDTGVIHVVEKEEDLQWVLTDGPNPPYMVLLESKHFTRDLMEKLKGRTSRIAG
LAVSLTKPSPASGFSPSVQCPNDGFGVYSNSYGPEFAHCREIQWNSLGNGLAYEDFSFPI
FLLEDENETKVIKQCYQDHNLSQNGSAPTFPLCAMQLFSHMHAVISTATCMRRSSIQSTF
SINPEIVCDPLSDYNVWSMLKPINTTGTLKPDDRVVVAATRLDSRSFFWNVAPGAESAVA
SFVTQLAAAEALQKAPDVTTLPRNVMFVFFQGETFDYIGSSRMVYDMEKGKFPVQLENVD
SFVELGQVALRTSLELWMHTDPVSQKNESVRNQVEDLLATLEKSGAGVPAVILRRPNQSQ
PLPPSSLQRFLRARNISGVVLADHSGAFHNKYYQSIYDTAENINVSYPEWLSPEEDLNFV
TDTAKALADVATVLGRALYELAGGTNFSDTVQADPQTVTRLLYGFLIKANNSWFQSILRQ
DLRSYLGDGPLQHYIAVSSPTNTTYVVQYALANLTGTVVNLTREQCQDPSKVPSENKDLY
EYSWVQGPLHSNETDRLPRCVRSTARLARALSPAFELSQWSSTEYSTWTESRWKDIRARI
FLIASKELELITLTVGFGILIFSLIVTYCINAKADVLFIAPREPGAVSY
Sequence of entity 2 (B), FASTA
>8K8E_2 Presenilin-1 (chains B)
MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPLSNGRPQGNSR
QVVEQDEEEDEELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTE
DTETVGQRALHSILNAAIMISVIVVMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFI
YLGEVFKTYNVAVDYITVALLIWNFGVVGMISIHWKGPLRLQQAYLIMISALMALVFIKY
LPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAE
GDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAA
VQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCL
TLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI
Sequence of entity 3 (C), FASTA
>8K8E_3 Gamma-secretase subunit APH-1A (chains C)
MGAAVFFGCTFVAFGPAFALFLITVAGDPLRVIILVAGAFFWLVSLLLASVVWFILVHVT
DRSDARLQYGLLIFGAAVSVLLQEVFRFAYYKLLKKADEGLASLSEDGRSPISIRQMAYV
SGLSFGIISGVFSVINILADALGPGVVGIHGDSPYYFLTSAFLTAAIILLHTFWGVVFFD
ACERRRYWALGLVVGSHLLTSGLTFLNPWYEASLLPIYAVTVSMGLWAFITAGGSLRSIQ
RSLLCRRQEDSRVMVYSALRIPPED
Sequence of entity 4 (D), FASTA
>8K8E_4 Gamma-secretase subunit PEN-2 (chains D)
MNLERVSNEEKLNLCRKYYLGGFAFLPFLWLVNIFWFFREAFLVPAYTEQSQIKGYVWRS
AVGFLFWVIVLTSWITIFQIYRPRWGALGDYLSFTIPLGTP
Sequence of entity 5 (H), FASTA
>8K8E_5 ZQN-GLY-AIB-VAL-VAL-ILE-AIB-PHE-VAL-AIB-GLY-GLY-GLY-VAL-JUU-LEU-VAL-NH2 (chains H)
VGAVVIAFVAGGGVXLVX
Ligands and cofactors
| ID | Name | Formula | Copies |
|---|
| NAG | 2-acetamido-2-deoxy-beta-D-glucopyranose | C8 H15 N O6 | 6 |
| PC1 | 1,2-diacyl-sn-glycero-3-phosphocholine | C44 H88 N O8 P | 1 |
| CLR | Cholesterol | C27 H46 O | 3 |
Primary citation
Familial Alzheimer mutations stabilize synaptotoxic gamma-secretase-substrate complexes. Devkota, S., Zhou, R., Nagarajan, V. et al. Cell Rep (2024) 43:113761-113761. DOI 10.1016/j.celrep.2024.113761 · PubMed
Other PDB entries of the same protein (UniProt Q92542 (AlphaFold model), which also has an AlphaFold model), best resolution first:
- 8KCS 2.4 Å, Cryo-EM structure of human gamma-secretase in complex with BMS906024
- 6IYC 2.6 Å, Recognition of the Amyloid Precursor Protein by Human gamma-secretase
- 7D8X 2.6 Å, CryoEM structure of human gamma-secretase in complex with E2012 and L685458
- 8KCT 2.6 Å, Cryo-EM structure of human gamma-secretase in complex with Nirogacestat
- 6IDF 2.7 Å, Cryo-EM structure of gamma secretase in complex with a Notch fragment
- 8KCU 2.7 Å, Cryo-EM structure of human gamma-secretase in complex with MK-0752
- 8KCO 2.8 Å, Cryo-EM structure of human gamma-secretase in complex with RO4929097
- 7Y5T 2.9 Å, CryoEM structure of PS1-containing gamma-secretase in complex with MRK-560
- 8X52 2.9 Å, Cryo-EM structure of human gamma-secretase in complex with Abeta49
- 8X54 2.9 Å, Cryo-EM structure of human gamma-secretase in complex with APP-C99
- 9K95 2.9 Å, Cryo-EM structure of human gamma-secretase in complex with compound E
- 6LR4 3.0 Å, Molecular basis for inhibition of human gamma-secretase by small molecule
Browse structure collections
About this viewer
MolViewer shows 8K8E directly in your browser with nothing to install. Switch between cartoon, ball-and-stick, spacefill and surface views, color by chain, secondary structure or B-factor, measure distances, angles and dihedrals, and share or embed the view.