Structure of PDB 3i25 Chain B Binding Site BS01

Receptor Information

>3i25 Chain B (length=373) Species: 9606 (Homo sapiens)

SFVEMVDNLRGKSGQGYYVEMTVGSPPQTLNILVDTGSSNFAVGAAPHPF
LHRYYQRQLSSTYRDLRKGVYVPYTQGKWEGELGTDLVSIPHGPNVTVRA
NIAAITESDKFFINGSNWEGILGLAYAEIARPDDSLEPFFDSLVKQTHVP
NLFSLQLCGASVGGSMIIGGIDHSLYTGSLWYTPIRREWYYEVIIVRVEI
NGQDLKMDCKEYNYDKSIVDSGTTNLRLPKKVFEAAVKSIKAASSTEKFP
DGFWLGEQLVCWQAGTTPWNIFPVISLYLMGEVTNQSFRITILPQQYLRP
VESQDDCYKFAISQSSTGTVMGAVIMEGFYVVFDRARKRIGFAVSACHVH
DEFRTAAVEGPFVTLDMEDCGYN

Ligand information

• Ligand ID: MV7
• InChI: InChI=1S/C45H55F2N5O10S/c1-28(2)41(45(57)48-26-30-13-9-7-10-14-30)51-44(56)40(61-18-17-60-5)25-39(53)38(27-62-37-23-34(46)22-35(47)24-37)50-43(55)33-19-32(20-36(21-33)52(4)63(6,58)59)42(54)49-29(3)31-15-11-8-12-16-31/h7-16,19-24,28-29,38-41,53H,17-18,25-27H2,1-6H3,(H,48,57)(H,49,54)(H,50,55)(H,51,56)/t29-,38+,39+,40-,41+/m1/s1
• InChIKey: RSTFVOGBJGGSOD-NDKACYJFSA-N
• SMILES:
  OpenEye OEToolkits 1.7.0: C[C@H](c1ccccc1)NC(=O)c2cc(cc(c2)N(C)S(=O)(=O)C)C(=O)N[C@@H](COc3cc(cc(c3)F)F)[C@H](C[C@H](C(=O)N[C@@H](C(C)C)C(=O)NCc4ccccc4)OCCOC)O
  CACTVS 3.370: COCCO[CH](C[CH](O)[CH](COc1cc(F)cc(F)c1)NC(=O)c2cc(cc(c2)C(=O)N[CH](C)c3ccccc3)N(C)[S](C)(=O)=O)C(=O)N[CH](C(C)C)C(=O)NCc4ccccc4
  OpenEye OEToolkits 1.7.0: CC(C)C(C(=O)NCc1ccccc1)NC(=O)C(CC(C(COc2cc(cc(c2)F)F)NC(=O)c3cc(cc(c3)N(C)S(=O)(=O)C)C(=O)NC(C)c4ccccc4)O)OCCOC
  CACTVS 3.370: COCCO[C@H](C[C@H](O)[C@H](COc1cc(F)cc(F)c1)NC(=O)c2cc(cc(c2)C(=O)N[C@H](C)c3ccccc3)N(C)[S](C)(=O)=O)C(=O)N[C@@H](C(C)C)C(=O)NCc4ccccc4
  ACDLabs 12.01: O=C(NCc1ccccc1)C(NC(=O)C(OCCOC)CC(O)C(NC(=O)c3cc(C(=O)NC(c2ccccc2)C)cc(N(C)S(=O)(=O)C)c3)COc4cc(F)cc(F)c4)C(C)C
• Formula: C45 H55 F2 N5 O10 S
• Name: N-[(2S,3S,5R)-1-(3,5-difluorophenoxy)-3-hydroxy-5-(2-methoxyethoxy)-6-[[(2S)-3-methyl-1-oxo-1-(phenylmethylamino)butan-2-yl]amino]-6-oxo-hexan-2-yl]-5-(methyl-methylsulfonyl-amino)-N'-[(1R)-1-phenylethyl]benzene-1,3-dicarboxamide;
  N-[(1S,2S,4R)-4-((S)-1-Benzylcarbamoyl-2-methyl-propylcarbamoyl)-1-(3,5-difluoro-phenoxymethyl)-2-hydroxy-4-(2-methoxy-ethoxy)-butyl]-5-(methanesulfonyl-methyl-amino)-N'-((R)-1-phenyl-ethyl)-isophthalamide
• ChEMBL: CHEMBL591644
• ZINC: ZINC000150344683
• PDB chain: 3i25 Chain B Residue 531

Receptor-Ligand Complex Structure

Structure summary

• PDB: 3i25 Discovery of potent BACE-1 inhibitors containing a new hydroxyethylene (HE) scaffold: exploration of P1' alkoxy residues and an aminoethylene (AE) central core
• Resolution: 2.1 Å
• Binding residue (original residue number in PDB): G11 Q12 G13 L30 D32 G34 P70 Y71 T72 Q73 G74 F108 I110 W115 I126 Y198 I226 D228 G230 T231 T232 N233 R235 T329
• Binding residue (residue number reindexed from 1): G14 Q15 G16 L33 D35 G37 P73 Y74 T75 Q76 G77 F111 I113 W118 I129 Y190 I218 D220 G222 T223 T224 N225 R227 T317
• Annotation score: 1
• Binding affinity: MOAD: Ki=3.1nM
  BindingDB: Ki=3.1nM

Enzymatic activity

• Catalytic site (original residue number in PDB): D32 S35 N37 A39 Y71 D228 T231
• Catalytic site (residue number reindexed from 1): D35 S38 N40 A42 Y74 D220 T223
• Enzyme Commision number: 3.4.23.46: memapsin 2.

Gene Ontology

Molecular Function

• GO:0004190 aspartic-type endopeptidase activity

Biological Process

• GO:0006508 proteolysis

Cellular Component

• GO:0016020 membrane

External links

• PDB: RCSB:3i25, PDBe:3i25, PDBj:3i25
• PDBsum: 3i25
• PubMed: 20122837
• UniProt: P56817|BACE1_HUMAN Beta-secretase 1 (Gene Name=BACE1)