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Fluorine in PDB 5hu1: BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide

Enzymatic activity of BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide

All present enzymatic activity of BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide:
3.4.23.46;

Protein crystallography data

The structure of BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide, PDB code: 5hu1 was solved by P.Orth, with X-Ray Crystallography technique. A brief refinement statistics is given in the table below:

Resolution Low / High (Å) 45.33 / 1.50
Space group P 21 21 21
Cell size a, b, c (Å), α, β, γ (°) 87.050, 90.200, 131.360, 90.00, 90.00, 90.00
R / Rfree (%) 18.5 / 20.1

Fluorine Binding Sites:

The binding sites of Fluorine atom in the BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide (pdb code 5hu1). This binding sites where shown within 5.0 Angstroms radius around Fluorine atom.
In total 4 binding sites of Fluorine where determined in the BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide, PDB code: 5hu1:
Jump to Fluorine binding site number: 1; 2; 3; 4;

Fluorine binding site 1 out of 4 in 5hu1

Go back to Fluorine Binding Sites List in 5hu1
Fluorine binding site 1 out of 4 in the BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 1 of BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F501

b:19.0
occ:1.00
 F18 A:66F501 0.0 19.0 1.0
C17 A:66F501 1.4 16.9 1.0
C1 A:66F501 2.4 14.6 1.0
C16 A:66F501 2.4 16.2 1.0
C2 A:66F501 2.9 14.8 1.0
C4 A:66F501 3.0 15.9 1.0
C3 A:66F501 3.0 15.6 1.0
CD2 A:TYR132 3.2 25.4 1.0
CE1 A:PHE169 3.3 22.1 1.0
CE2 A:TYR132 3.3 24.9 1.0
CD1 A:PHE169 3.5 22.2 1.0
C13 A:66F501 3.6 13.7 1.0
C15 A:66F501 3.6 17.3 1.0
O12 A:66F501 3.7 19.2 1.0
S5 A:66F501 4.0 20.2 1.0
C14 A:66F501 4.1 15.8 1.0
CG A:TYR132 4.1 25.8 1.0
CZ A:TYR132 4.2 31.1 1.0
CD1 A:ILE179 4.3 18.0 1.0
N8 A:66F501 4.3 13.2 1.0
CZ A:PHE169 4.5 20.7 1.0
CB A:TYR132 4.8 26.2 1.0
CG A:PHE169 4.9 21.5 1.0
CD1 A:TYR132 4.9 26.9 1.0
OH A:TYR132 4.9 32.6 1.0
O A:HOH658 4.9 26.8 1.0
CE1 A:TYR132 5.0 26.4 1.0

Fluorine binding site 2 out of 4 in 5hu1

Go back to Fluorine Binding Sites List in 5hu1
Fluorine binding site 2 out of 4 in the BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 2 of BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F501

b:16.7
occ:1.00
 F28 A:66F501 0.0 16.7 1.0
C21 A:66F501 1.3 13.8 1.0
C22 A:66F501 2.4 13.4 1.0
C20 A:66F501 2.4 15.6 1.0
O A:SER71 2.8 16.7 1.0
CB A:ALA396 3.5 13.3 1.0
N23 A:66F501 3.6 14.5 1.0
C A:SER71 3.6 14.9 1.0
OG1 A:THR293 3.6 14.5 1.0
C25 A:66F501 3.6 16.3 1.0
CA A:GLY74 3.7 12.8 1.0
CA A:SER71 3.8 12.7 1.0
N A:GLY74 3.8 13.3 1.0
CA A:THR293 3.8 11.6 1.0
O A:THR292 4.0 13.2 1.0
C24 A:66F501 4.1 15.2 1.0
N A:THR293 4.1 12.3 1.0
O A:LYS70 4.1 13.9 1.0
C A:THR292 4.2 14.3 1.0
O A:SER290 4.2 12.5 1.0
CB A:THR293 4.3 14.4 1.0
O A:HOH785 4.6 14.4 1.0
CB A:SER71 4.6 14.9 1.0
C A:GLN73 4.7 18.5 1.0
C A:GLY74 4.8 13.6 1.0
N A:GLY72 4.8 15.1 1.0
N A:SER71 4.8 13.1 1.0
CA A:ALA396 4.9 11.5 1.0
C A:LYS70 4.9 14.4 1.0
N A:GLN73 4.9 16.3 1.0
CD2 A:TYR75 4.9 13.2 1.0
CG2 A:THR293 4.9 13.2 1.0
N A:THR292 5.0 12.1 1.0
C A:GLY72 5.0 19.6 1.0
N A:TYR75 5.0 11.4 1.0

Fluorine binding site 3 out of 4 in 5hu1

Go back to Fluorine Binding Sites List in 5hu1
Fluorine binding site 3 out of 4 in the BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 3 of BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide within 5.0Å range:
probe atom residue distance (Å) B Occ
B:F501

b:20.2
occ:1.00
 F18 B:66F501 0.0 20.2 1.0
C17 B:66F501 1.3 19.4 1.0
C16 B:66F501 2.3 18.1 1.0
C1 B:66F501 2.4 15.4 1.0
C2 B:66F501 2.9 14.5 1.0
C3 B:66F501 3.0 16.1 1.0
C4 B:66F501 3.0 16.4 1.0
CE1 B:PHE169 3.3 19.0 1.0
CD2 B:TYR132 3.4 26.5 1.0
CD1 B:PHE169 3.5 19.3 1.0
CE2 B:TYR132 3.5 26.8 1.0
C13 B:66F501 3.6 14.7 1.0
C15 B:66F501 3.6 18.1 1.0
O12 B:66F501 3.8 19.5 1.0
C14 B:66F501 4.1 16.0 1.0
S5 B:66F501 4.1 20.1 1.0
CD1 B:ILE179 4.2 19.0 1.0
N8 B:66F501 4.3 14.8 1.0
CG B:TYR132 4.4 26.0 1.0
CZ B:TYR132 4.5 33.0 1.0
CZ B:PHE169 4.6 17.3 1.0
CD1 B:TRP137 4.7 21.2 1.0
CG B:PHE169 4.8 17.1 1.0
O B:GLY135 4.8 35.8 1.0
O B:HOH644 4.9 23.6 1.0
NE1 B:TRP137 5.0 19.9 1.0
CB B:TYR132 5.0 24.5 1.0

Fluorine binding site 4 out of 4 in 5hu1

Go back to Fluorine Binding Sites List in 5hu1
Fluorine binding site 4 out of 4 in the BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 4 of BACE1 in Complex with (R)-N-(3-(3-Amino-2,5-Dimethyl-1,1-Dioxido-5,6- Dihydro-2H-1,2,4-Thiadiazin-5-Yl)-4-Fluorophenyl)-5- Fluoropicolinamide within 5.0Å range:
probe atom residue distance (Å) B Occ
B:F501

b:17.0
occ:1.00
 F28 B:66F501 0.0 17.0 1.0
C21 B:66F501 1.4 15.5 1.0
C22 B:66F501 2.4 13.7 1.0
C20 B:66F501 2.4 17.0 1.0
O B:SER71 2.9 15.4 1.0
CB B:ALA396 3.5 12.5 1.0
N23 B:66F501 3.6 14.1 1.0
CA B:GLY74 3.6 14.0 1.0
OG1 B:THR293 3.7 15.1 1.0
C25 B:66F501 3.7 17.8 1.0
C B:SER71 3.7 14.6 1.0
N B:GLY74 3.7 14.8 1.0
CA B:SER71 3.9 13.3 1.0
CA B:THR293 3.9 12.2 1.0
O B:THR292 4.0 12.6 1.0
C24 B:66F501 4.0 15.2 1.0
N B:THR293 4.1 12.2 1.0
O B:SER290 4.1 13.5 1.0
C B:THR292 4.1 13.9 1.0
O B:LYS70 4.1 14.1 1.0
CB B:THR293 4.3 14.5 1.0
O B:HOH776 4.5 14.8 1.0
C B:GLN73 4.6 18.9 1.0
C B:GLY74 4.7 14.1 1.0
CB B:SER71 4.7 13.5 1.0
N B:GLY72 4.8 14.2 1.0
N B:GLN73 4.9 15.4 1.0
N B:SER71 4.9 13.1 1.0
N B:TYR75 4.9 12.3 1.0
CA B:ALA396 4.9 11.7 1.0
N B:THR292 4.9 13.3 1.0
C B:LYS70 4.9 14.8 1.0
CD1 B:TYR75 4.9 13.9 1.0
CG2 B:THR293 5.0 13.8 1.0
C B:GLY72 5.0 17.8 1.0

Reference:

J.D.Scott, S.W.Li, A.P.Brunskill, X.Chen, K.Cox, J.N.Cumming, M.Forman, E.J.Gilbert, R.A.Hodgson, L.A.Hyde, Q.Jiang, U.Iserloh, I.Kazakevich, R.Kuvelkar, H.Mei, J.Meredith, J.Misiaszek, P.Orth, L.M.Rossiter, M.Slater, J.Stone, C.O.Strickland, J.H.Voigt, G.Wang, H.Wang, Y.Wu, W.J.Greenlee, E.M.Parker, M.E.Kennedy, A.W.Stamford. Discovery of the 3-Imino-1,2,4-Thiadiazinane 1,1-Dioxide Derivative Verubecestat (Mk-8931)-A Beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 Inhibitor For the Treatment of Alzheimer'S Disease. J. Med. Chem. V. 59 10435 2016.
ISSN: ISSN 1520-4804
PubMed: 27933948
DOI: 10.1021/ACS.JMEDCHEM.6B00307
Page generated: Sun Dec 13 12:24:01 2020

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