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Fluorine in PDB 5he4: Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium

Enzymatic activity of Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium

All present enzymatic activity of Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium:
3.4.23.46;

Protein crystallography data

The structure of Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium, PDB code: 5he4 was solved by P.Orth, with X-Ray Crystallography technique. A brief refinement statistics is given in the table below:

Resolution Low / High (Å) 19.90 / 1.53
Space group P 21 21 21
Cell size a, b, c (Å), α, β, γ (°) 86.390, 89.370, 131.240, 90.00, 90.00, 90.00
R / Rfree (%) 20.3 / 22.2

Fluorine Binding Sites:

The binding sites of Fluorine atom in the Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium (pdb code 5he4). This binding sites where shown within 5.0 Angstroms radius around Fluorine atom.
In total 6 binding sites of Fluorine where determined in the Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium, PDB code: 5he4:
Jump to Fluorine binding site number: 1; 2; 3; 4; 5; 6;

Fluorine binding site 1 out of 6 in 5he4

Go back to Fluorine Binding Sites List in 5he4
Fluorine binding site 1 out of 6 in the Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 1 of Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F501

b:17.5
occ:1.00
 F2 A:60T501 0.0 17.5 1.0
C17 A:60T501 1.3 16.0 1.0
C16 A:60T501 2.3 19.3 1.0
C12 A:60T501 2.4 15.0 1.0
N3 A:60T501 2.6 14.1 1.0
C6 A:60T501 2.9 14.3 1.0
C7 A:60T501 2.9 13.0 1.0
O A:GLY291 3.2 12.9 1.0
CA A:GLY291 3.2 10.0 1.0
N4 A:60T501 3.3 11.9 1.0
OD2 A:ASP93 3.4 13.8 1.0
CG A:ASP93 3.4 14.5 1.0
OD1 A:ASP93 3.5 12.2 1.0
C A:GLY291 3.5 13.9 1.0
C15 A:60T501 3.6 20.2 1.0
C13 A:60T501 3.6 19.8 1.0
N5 A:60T501 3.7 15.3 1.0
CD2 A:LEU91 3.7 22.8 1.0
C5 A:60T501 4.0 15.6 1.0
O A:HOH825 4.0 32.7 1.0
C14 A:60T501 4.1 19.5 1.0
C10 A:60T501 4.2 16.0 1.0
CB A:ASP93 4.2 11.8 1.0
C9 A:60T501 4.3 19.7 1.0
CD1 A:ILE179 4.4 20.3 1.0
N A:GLY291 4.5 10.8 1.0
O A:HOH787 4.6 29.6 1.0
C8 A:60T501 4.6 14.3 1.0
F1 A:60T501 4.7 21.7 1.0
N A:THR292 4.8 11.3 1.0
CG A:LEU91 5.0 18.9 1.0

Fluorine binding site 2 out of 6 in 5he4

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Fluorine binding site 2 out of 6 in the Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 2 of Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F501

b:21.7
occ:1.00
 F1 A:60T501 0.0 21.7 1.0
C13 A:60T501 1.3 19.8 1.0
C14 A:60T501 2.3 19.5 1.0
C12 A:60T501 2.4 15.0 1.0
C6 A:60T501 2.9 14.3 1.0
OH A:TYR132 3.0 49.2 1.0
C10 A:60T501 3.0 16.0 1.0
C5 A:60T501 3.0 15.6 1.0
CZ A:TYR132 3.1 46.0 1.0
CE2 A:TYR132 3.3 39.1 1.0
CE1 A:PHE169 3.5 25.5 1.0
CD1 A:PHE169 3.5 25.7 1.0
C15 A:60T501 3.6 20.2 1.0
C17 A:60T501 3.6 16.0 1.0
O A:HOH840 3.7 51.6 1.0
CE1 A:TYR132 3.7 40.0 1.0
N2 A:60T501 3.9 17.3 1.0
C11 A:60T501 3.9 19.2 1.0
C9 A:60T501 4.1 19.7 1.0
C16 A:60T501 4.1 19.3 1.0
CD1 A:ILE179 4.1 20.3 1.0
CD2 A:TYR132 4.2 38.5 1.0
N3 A:60T501 4.3 14.1 1.0
CD1 A:TYR132 4.5 39.9 1.0
O1 A:60T501 4.6 23.1 1.0
CG A:PHE169 4.7 23.8 1.0
CZ A:PHE169 4.7 22.6 1.0
CG A:TYR132 4.7 37.9 1.0
F2 A:60T501 4.7 17.5 1.0
O A:HOH669 4.7 38.4 1.0
C2 A:60T501 4.8 19.5 1.0
N5 A:60T501 5.0 15.3 1.0

Fluorine binding site 3 out of 6 in 5he4

Go back to Fluorine Binding Sites List in 5he4
Fluorine binding site 3 out of 6 in the Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 3 of Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium within 5.0Å range:
probe atom residue distance (Å) B Occ
A:F501

b:23.5
occ:1.00
 F A:60T501 0.0 23.5 1.0
C A:60T501 1.3 22.1 1.0
C3 A:60T501 2.4 23.5 1.0
C1 A:60T501 2.4 19.5 1.0
O A:60T501 2.7 27.9 1.0
C18 A:60T501 2.9 19.3 1.0
O A:HOH837 3.0 17.5 1.0
OD1 A:ASN98 3.0 16.8 1.0
CG A:ASN98 3.4 18.5 1.0
N1 A:60T501 3.6 20.7 1.0
CG A:ARG189 3.6 23.4 1.0
N A:60T501 3.6 18.8 1.0
CB A:ASN98 3.7 13.2 1.0
CZ2 A:TRP137 3.8 26.1 1.0
CG1 A:VAL130 3.9 32.9 1.0
CG2 A:VAL130 4.0 32.9 1.0
C2 A:60T501 4.0 19.5 1.0
CB A:ARG189 4.0 18.9 1.0
C4 A:60T501 4.1 26.5 1.0
ND2 A:ASN98 4.4 15.0 1.0
CB A:VAL130 4.5 32.9 1.0
CE2 A:TRP137 4.6 28.3 1.0
N A:ASN98 4.6 11.5 1.0
N A:ARG189 4.6 16.5 1.0
NE1 A:TRP137 4.6 28.5 1.0
CH2 A:TRP137 4.7 24.9 1.0
CA A:ASN98 4.8 11.4 1.0
CB A:SER96 4.8 13.0 1.0
CD A:ARG189 4.9 31.2 1.0
CA A:ARG189 5.0 16.9 1.0

Fluorine binding site 4 out of 6 in 5he4

Go back to Fluorine Binding Sites List in 5he4
Fluorine binding site 4 out of 6 in the Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 4 of Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium within 5.0Å range:
probe atom residue distance (Å) B Occ
B:F502

b:14.6
occ:1.00
 F2 B:60T502 0.0 14.6 1.0
C17 B:60T502 1.4 13.5 1.0
C16 B:60T502 2.3 15.2 1.0
C12 B:60T502 2.4 11.8 1.0
N3 B:60T502 2.6 13.3 1.0
C7 B:60T502 2.9 12.1 1.0
C6 B:60T502 2.9 11.6 1.0
O B:GLY291 3.1 13.2 1.0
CA B:GLY291 3.2 10.9 1.0
N4 B:60T502 3.3 11.8 1.0
CD2 B:LEU91 3.4 21.3 1.0
OD2 B:ASP93 3.5 13.2 1.0
C B:GLY291 3.5 12.5 1.0
CG B:ASP93 3.6 13.0 1.0
C15 B:60T502 3.6 17.0 1.0
C13 B:60T502 3.6 14.0 1.0
OD1 B:ASP93 3.7 11.3 1.0
N5 B:60T502 3.7 13.1 1.0
O B:HOH817 3.9 26.4 1.0
C5 B:60T502 4.0 13.4 1.0
C14 B:60T502 4.1 15.4 1.0
C10 B:60T502 4.2 12.4 1.0
C9 B:60T502 4.3 16.9 1.0
CB B:ASP93 4.3 10.4 1.0
CD1 B:ILE179 4.4 16.0 1.0
N B:GLY291 4.5 10.8 1.0
C8 B:60T502 4.6 14.7 1.0
O B:HOH822 4.7 27.6 1.0
F1 B:60T502 4.7 16.5 1.0
N B:THR292 4.7 10.9 1.0
CG B:LEU91 4.8 17.3 1.0

Fluorine binding site 5 out of 6 in 5he4

Go back to Fluorine Binding Sites List in 5he4
Fluorine binding site 5 out of 6 in the Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 5 of Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium within 5.0Å range:
probe atom residue distance (Å) B Occ
B:F502

b:16.5
occ:1.00
 F1 B:60T502 0.0 16.5 1.0
C13 B:60T502 1.3 14.0 1.0
C14 B:60T502 2.3 15.4 1.0
C12 B:60T502 2.3 11.8 1.0
C6 B:60T502 2.8 11.6 1.0
OH B:TYR132 2.9 27.8 1.0
C10 B:60T502 3.0 12.4 1.0
C5 B:60T502 3.0 13.4 1.0
CZ B:TYR132 3.2 28.2 1.0
O B:HOH748 3.4 36.5 1.0
CD1 B:PHE169 3.4 21.9 1.0
CE2 B:TYR132 3.6 23.0 1.0
C15 B:60T502 3.6 17.0 1.0
C17 B:60T502 3.6 13.5 1.0
CE1 B:PHE169 3.7 21.7 1.0
N2 B:60T502 3.8 14.4 1.0
C11 B:60T502 3.9 14.7 1.0
CE1 B:TYR132 3.9 24.9 1.0
C9 B:60T502 4.1 16.9 1.0
CD1 B:ILE179 4.1 16.0 1.0
C16 B:60T502 4.1 15.2 1.0
O B:HOH918 4.2 51.3 1.0
N3 B:60T502 4.3 13.3 1.0
CG B:PHE169 4.4 19.6 1.0
CD2 B:TYR132 4.5 22.3 1.0
O1 B:60T502 4.6 19.7 1.0
CA B:PHE169 4.7 18.6 1.0
F2 B:60T502 4.7 14.6 1.0
O B:HOH907 4.7 34.4 1.0
O B:PHE169 4.8 24.8 1.0
CD1 B:TYR132 4.8 25.0 1.0
C2 B:60T502 4.8 14.2 1.0
CZ B:PHE169 4.8 19.3 1.0
CB B:PHE169 4.9 19.5 1.0
N5 B:60T502 5.0 13.1 1.0
O B:HOH1089 5.0 42.6 1.0

Fluorine binding site 6 out of 6 in 5he4

Go back to Fluorine Binding Sites List in 5he4
Fluorine binding site 6 out of 6 in the Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium


Mono view


Stereo pair view

A full contact list of Fluorine with other atoms in the F binding site number 6 of Bace-1 in Complex with (4AR,7AS)-7A-(2,6-Difluorophenyl)-6-(5-Fluoro- 4-Methoxy-6-Methylpyrimidin-2-Yl)-3-Methyl-4-Oxooctahydro-2H- Pyrrolo[3,4-D]Pyrimidin-2-Iminium within 5.0Å range:
probe atom residue distance (Å) B Occ
B:F502

b:18.1
occ:1.00
 F B:60T502 0.0 18.1 1.0
C B:60T502 1.3 14.4 1.0
C3 B:60T502 2.4 14.8 1.0
C1 B:60T502 2.4 13.9 1.0
O B:60T502 2.7 15.7 1.0
C18 B:60T502 2.9 13.6 1.0
O B:HOH801 3.0 13.7 1.0
OD1 B:ASN98 3.0 13.6 1.0
CG B:ASN98 3.4 15.5 1.0
CB B:ASN98 3.6 11.8 1.0
N1 B:60T502 3.6 14.5 1.0
CZ2 B:TRP137 3.6 18.0 1.0
N B:60T502 3.6 14.1 1.0
CG B:ARG189 3.7 16.9 1.0
C2 B:60T502 4.0 14.2 1.0
C4 B:60T502 4.1 16.4 1.0
CB B:ARG189 4.1 14.7 1.0
CG1 B:VAL130 4.1 17.9 1.0
NE1 B:TRP137 4.2 18.6 1.0
CG2 B:VAL130 4.2 19.0 1.0
CE2 B:TRP137 4.3 18.2 1.0
ND2 B:ASN98 4.4 13.4 1.0
N B:ASN98 4.4 9.5 1.0
CB B:SER96 4.6 13.0 1.0
CH2 B:TRP137 4.6 16.7 1.0
CA B:ASN98 4.6 9.2 1.0
N B:ARG189 4.7 13.6 1.0
CB B:VAL130 4.7 18.2 1.0
N B:SER97 5.0 9.5 1.0

Reference:

M.Mandal, Y.Wu, J.Misiaszek, G.Li, A.Buevich, J.P.Caldwell, X.Liu, R.D.Mazzola, P.Orth, C.Strickland, J.Voigt, H.Wang, Z.Zhu, X.Chen, M.Grzelak, L.A.Hyde, R.Kuvelkar, P.T.Leach, G.Terracina, L.Zhang, Q.Zhang, M.S.Michener, B.Smith, K.Cox, D.Grotz, L.Favreau, K.Mitra, I.Kazakevich, B.A.Mckittrick, W.Greenlee, M.E.Kennedy, E.M.Parker, J.N.Cumming, A.W.Stamford. Structure-Based Design of An Iminoheterocyclic Beta-Site Amyloid Precursor Protein Cleaving Enzyme (Bace) Inhibitor That Lowers Central A Beta in Nonhuman Primates. J.Med.Chem. V. 59 3231 2016.
ISSN: ISSN 0022-2623
PubMed: 26937601
DOI: 10.1021/ACS.JMEDCHEM.5B01995
Page generated: Thu Aug 1 09:50:14 2024

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