6LR4: Nicastrin

Molecular basis for inhibition of human gamma-secretase by small molecule. Determined by electron microscopy at 3.0 Å resolution. Released 27 Jan 2021.

Method
Electron microscopy
Resolution
3.0 Å
Organism
Homo sapiens
Chains
4
Atoms
10,838
Mol. weight
184.18 kDa
Ligands
NAG, ESF, CLR, PC1
Released
27 Jan 2021

Explore 6LR4 in 3D Show helices and sheets RCSB PDB PDBe

Secondary structure: helices and β-sheets

6LR4 contains 59 α-helices and 32 β-strands across 4 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: 27 helices, 27 β-strands

ElementResiduesLengthSheet
α-helix37-393
β-strand42-4321
β-strand47-4821
β-strand53-5422
β-strand59-6022
β-strand6113
α-helix64-652
β-strand69-7571
α-helix79-813
α-helix82-832
α-helix84-885
β-strand94-9961
α-helix105-1128
β-strand118-12471
α-helix125-1262
β-strand13514
α-helix143-1453
β-strand16814
α-helix171-1733
β-strand17513
β-strand180-18341
α-helix186-19914
α-helix207-2093
β-strand212-21871
α-helix227-23913
β-strand248-25032
β-strand253-25975
β-strand275-28175
α-helix295-2995
α-helix300-31314
β-strand324-33075
α-helix338-34710
β-strand359-36575
β-strand375-37955
α-helix384-3863
α-helix388-40518
β-strand412-41435
α-helix427-4304
β-strand437-44265
α-helix479-4813
α-helix482-50221
α-helix515-52612
α-helix541-5455
α-helix562-57514
β-strand577-57936
α-helix583-5875
α-helix589-5913
β-strand601-60556
β-strand619-62356
β-strand626-63055
β-strand649-65132
β-strand657-66371
α-helix666-69227
α-helix694-6974
Chain B: 14 helices, 3 β-strands
ElementResiduesLengthSheet
α-helix83-10321
α-helix125-15531
α-helix160-17112
α-helix172-1776
α-helix178-18811
β-strand193-19427
α-helix195-21420
α-helix219-23921
α-helix243-26220
α-helix267-27610
β-strand28718
β-strand38218
α-helix383-39816
α-helix405-42824
α-helix435-44814
α-helix449-4535
α-helix454-46310
Chain C: 12 helices, 1 β-strand
ElementResiduesLengthSheet
α-helix3-1311
α-helix15-206
α-helix21-255
α-helix31-6030
α-helix66-10136
α-helix114-13926
β-strand14611
α-helix156-18328
α-helix188-20215
α-helix203-2053
α-helix210-2123
α-helix215-23117
α-helix236-2394
Chain D: 6 helices, 1 β-strand
ElementResiduesLengthSheet
α-helix8-1912
α-helix27-3610
α-helix381
α-helix39-435
α-helix50-8031
α-helix88-914
β-strand93-9537

Molecules and chains

MoleculeChainsTypeLengthOrganismUniProt
NicastrinAprotein709Homo sapiensQ92542 (AlphaFold model)
Presenilin-1Bprotein467Homo sapiensP49768 (AlphaFold model)
Gamma-secretase subunit APH-1ACprotein265Homo sapiensQ96BI3 (AlphaFold model)
Gamma-secretase subunit PEN-2Dprotein143Homo sapiensQ9NZ42 (AlphaFold model)
Sequence of entity 1 (A), FASTA
>6LR4_1 Nicastrin (chains A)
MATAGGGSGADPGSRGLLRLLSFCVLLAGLCRGNSVERKIYIPLNKTAPCVRLLNATHQI
GCQSSISGDTGVIHVVEKEEDLQWVLTDGPNPPYMVLLESKHFTRDLMEKLKGRTSRIAG
LAVSLTKPSPASGFSPSVQCPNDGFGVYSNSYGPEFAHCREIQWNSLGNGLAYEDFSFPI
FLLEDENETKVIKQCYQDHNLSQNGSAPTFPLCAMQLFSHMHAVISTATCMRRSSIQSTF
SINPEIVCDPLSDYNVWSMLKPINTTGTLKPDDRVVVAATRLDSRSFFWNVAPGAESAVA
SFVTQLAAAEALQKAPDVTTLPRNVMFVFFQGETFDYIGSSRMVYDMEKGKFPVQLENVD
SFVELGQVALRTSLELWMHTDPVSQKNESVRNQVEDLLATLEKSGAGVPAVILRRPNQSQ
PLPPSSLQRFLRARNISGVVLADHSGAFHNKYYQSIYDTAENINVSYPEWLSPEEDLNFV
TDTAKALADVATVLGRALYELAGGTNFSDTVQADPQTVTRLLYGFLIKANNSWFQSILRQ
DLRSYLGDGPLQHYIAVSSPTNTTYVVQYALANLTGTVVNLTREQCQDPSKVPSENKDLY
EYSWVQGPLHSNETDRLPRCVRSTARLARALSPAFELSQWSSTEYSTWTESRWKDIRARI
FLIASKELELITLTVGFGILIFSLIVTYCINAKADVLFIAPREPGAVSY
Sequence of entity 2 (B), FASTA
>6LR4_2 Presenilin-1 (chains B)
MTELPAPLSYFQNAQMSEDNHLSNTVRSQNDNRERQEHNDRRSLGHPEPLSNGRPQGNSR
QVVEQDEEEDEELTLKYGAKHVIMLFVPVTLCMVVVVATIKSVSFYTRKDGQLIYTPFTE
DTETVGQRALHSILNAAIMISVIVVMTILLVVLYKYRCYKVIHAWLIISSLLLLFFFSFI
YLGEVFKTYNVAVDYITVALLIWNFGVVGMISIHWKGPLRLQQAYLIMISALMALVFIKY
LPEWTAWLILAVISVYDLVAVLCPKGPLRMLVETAQERNETLFPALIYSSTMVWLVNMAE
GDPEAQRRVSKNSKYNAESTERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAA
VQELSSSILAGEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCL
TLLLLAIFKKALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI
Sequence of entity 3 (C), FASTA
>6LR4_3 Gamma-secretase subunit APH-1A (chains C)
MGAAVFFGCTFVAFGPAFALFLITVAGDPLRVIILVAGAFFWLVSLLLASVVWFILVHVT
DRSDARLQYGLLIFGAAVSVLLQEVFRFAYYKLLKKADEGLASLSEDGRSPISIRQMAYV
SGLSFGIISGVFSVINILADALGPGVVGIHGDSPYYFLTSAFLTAAIILLHTFWGVVFFD
ACERRRYWALGLVVGSHLLTSGLTFLNPWYEASLLPIYAVTVSMGLWAFITAGGSLRSIQ
RSLLCRRQEDSRVMVYSALRIPPED
Sequence of entity 4 (D), FASTA
>6LR4_4 Gamma-secretase subunit PEN-2 (chains D)
MASWSHPQFEKGGGARGGSGGGSWSHPQFEKGFDYKDDDDKGTNLERVSNEEKLNLCRKY
YLGGFAFLPFLWLVNIFWFFREAFLVPAYTEQSQIKGYVWRSAVGFLFWVIVLTSWITIF
QIYRPRWGALGDYLSFTIPLGTP

Ligands and cofactors

IDNameFormulaCopies
NAG2-acetamido-2-deoxy-beta-D-glucopyranoseC8 H15 N O66
ESF(2S)-2-hydroxy-3-methyl-N-[(2S)-1-[[(5S)-3-methyl-4-oxo-2,5-dihydro-1H-3-benzaz…C19 H27 N3 O41
CLRCholesterolC27 H46 O3
PC11,2-diacyl-sn-glycero-3-phosphocholineC44 H88 N O8 P2

Primary citation

Structural basis of gamma-secretase inhibition and modulation by small molecule drugs. Yang, G., Zhou, R., Guo, X. et al. Cell (2021) 184:521-533.e14. DOI 10.1016/j.cell.2020.11.049 · PubMed

Other PDB entries of the same protein (UniProt Q92542 (AlphaFold model), which also has an AlphaFold model), best resolution first:

Browse structure collections

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