Target Binding Site Detail

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Target General Information
Ligand General Information
Drug Binding Sites of Target
References
Target General Information  Top
Target ID T03500 Target Info
Target Name Matrix metalloproteinase-12 (MMP-12)
Synonyms Macrophage metalloelastase; Macrophage elastase; MME; ME; HME
Target Type Clinical trial Target
Gene Name MMP12
Biochemical Class Peptidase
UniProt ID
MMP12_HUMAN
Ligand General Information  Top
Ligand Name RXP470.1 Ligand Info
Canonical SMILES C1=CC(=CC(=C1)Cl)C2=CC=C(C=C2)C3=NOC(=C3)CC(CP(=O)(C4=CC=C(C=C4)Br)O)C(=O)NC(CCC(=O)O)C(=O)NC(CCC(=O)O)C(=O)N
InChI 1S/C35H35BrClN4O10P/c36-24-8-10-27(11-9-24)52(49,50)19-23(34(47)40-29(13-15-32(44)45)35(48)39-28(33(38)46)12-14-31(42)43)17-26-18-30(41-51-26)21-6-4-20(5-7-21)22-2-1-3-25(37)16-22/h1-11,16,18,23,28-29H,12-15,17,19H2,(H2,38,46)(H,39,48)(H,40,47)(H,42,43)(H,44,45)(H,49,50)/t23-,28+,29+/m1/s1
InChIKey PTUCPHGSAFOJAU-MGONOCMRSA-N
PubChem Compound ID 44580458
Drug Binding Sites of Target  Top
PDB ID: 4GQL      Crystal structure of the catalytic domain of Human MMP12 in complex with selective phosphinic inhibitor RXP470.1
Method X-ray diffraction Resolution 1.15 Å Mutation Yes [1]
PDB Sequence
MGPVWRKHYI
114
TYRINNYTPD
124
MNREDVDYAI
134
RKAFQVWSNV
144
TPLKFSKINT
154

GMADILVVFA
164
RGAHGDDHAF
174
DGKGGILAHA
184
FGPGSGIGGD
194
AHFDEDEFWT
204

THSGGTNLFL
214
TAVHEIGHSL
224
GLGHSSDPKA
234
VMFPTYKYVD
244
INTFRLSADD
254

IRGIQSLYG
Residue
Distance (Å)
HIS172
3.521
GLY178
2.731
GLY179
2.166
ILE180
2.560
LEU181
1.992
ALA182
2.487
HIS183
2.554
ALA184
4.126
GLU201
4.480
THR210
4.038
LEU214
2.518
THR215
2.358
HIS218
2.987
GLU219
2.506
HIS222
2.895
Residue
Distance (Å)
HIS228
2.521
ASP231
4.942
PRO232
2.688
LYS233
2.976
ALA234
3.383
VAL235
2.589
MET236
4.694
PHE237
2.676
PRO238
2.807
THR239
2.411
TYR240
2.109
LYS241
2.873
VAL243
2.755
PHE248
2.809
PDB ID: 5CZM      Crystal structure of a mutated catalytic domain of Human MMP12 in complex with RXP470
Method X-ray diffraction Resolution 1.30 Å Mutation Yes [2]
PDB Sequence
MGPVWRKHYI
114
TYRINNYTPD
124
MNREDVDYAI
134
RKAFQVWSNV
144
TPLKFSKINT
154

GMADILVVFA
164
RGAHGDDHAF
174
DGKGGILAHA
184
FGPGSGIGGD
194
AHFDEDEFWT
204

THSGGTNLFL
214
TAVHEIGHSL
224
GLGHSSDPKA
234
VMFPTYAYVD
244
INTFRLSADD
254

IRGIQSLYG
Residue
Distance (Å)
HIS172
3.519
GLY178
3.617
GLY179
2.916
ILE180
3.500
LEU181
2.789
ALA182
3.326
HIS183
3.460
ALA184
4.632
GLU201
4.439
THR210
4.599
LEU214
3.897
THR215
3.246
HIS218
3.341
GLU219
2.869
Residue
Distance (Å)
HIS222
3.406
HIS228
2.943
PRO232
3.268
LYS233
3.620
ALA234
3.613
VAL235
3.312
PHE237
3.229
PRO238
3.349
THR239
3.090
TYR240
2.829
ALA241
3.732
VAL243
3.418
PHE248
3.216
ARG249
4.737
PDB ID: 5L7F      Crystal structure of MMP12 mutant K421A in complex with RXP470.1 conjugated with fluorophore Cy5,5 in space group P21.
Method X-ray diffraction Resolution 1.80 Å Mutation Yes [3]
PDB Sequence
GPVWRKHYIT
115
YRINNYTPDM
125
NREDVDYAIR
135
KAFQVWSNVT
145
PLKFSKINTG
155

MADILVVFAR
165
GAHGDDHAFD
175
GKGGILAHAF
185
GPGSGIGGDA
195
HFDEDEFWTT
205

HSGGTNLFLT
215
AVHEIGHSLG
225
LGHSSDPKAV
235
MFPTYAYVDI
245
NTFRLSADDI
255

RGIQSLYG
Residue
Distance (Å)
HIS172
4.499
GLY178
3.711
GLY179
2.967
ILE180
3.548
LEU181
2.871
ALA182
3.466
HIS183
3.759
ALA184
4.666
GLU201
4.446
THR210
4.506
LEU214
3.913
THR215
3.191
HIS218
3.333
GLU219
2.681
Residue
Distance (Å)
HIS222
3.411
HIS228
2.886
PRO232
3.135
LYS233
3.582
ALA234
2.943
VAL235
3.315
PHE237
3.193
PRO238
3.040
THR239
3.137
TYR240
2.848
ALA241
3.271
TYR242
3.920
VAL243
3.375
PHE248
4.392
PDB ID: 5L79      Crystal structure of MMP12 in complex with RXP470.1 conjugated with fluorophore Cy5,5 in space group P21212.
Method X-ray diffraction Resolution 2.07 Å Mutation Yes [3]
PDB Sequence
MGPVWRKHYI
114
TYRINNYTPD
124
MNREDVDYAI
134
RKAFQVWSNV
144
TPLKFSKINT
154

GMADILVVFA
164
RGAHGDDHAF
174
DGKGGILAHA
184
FGPGSGIGGD
194
AHFDEDEFWT
204

THSGGTNLFL
214
TAVHEIGHSL
224
GLGHSSDPKA
234
VMFPTYKYVD
244
INTFRLSADD
254

IRGIQSLYG
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .R47 or .R472 or .R473 or :3R47;style chemicals stick;color identity;select .A:172 or .A:178 or .A:179 or .A:180 or .A:181 or .A:182 or .A:183 or .A:184 or .A:201 or .A:214 or .A:215 or .A:218 or .A:219 or .A:222 or .A:228 or .A:232 or .A:233 or .A:234 or .A:235 or .A:237 or .A:238 or .A:239 or .A:240 or .A:241 or .A:243 or .A:248 or .A:249; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
Residue
Distance (Å)
HIS172
4.334
GLY178
3.559
GLY179
2.807
ILE180
3.854
LEU181
2.914
ALA182
3.176
HIS183
3.545
ALA184
4.535
GLU201
4.567
LEU214
3.872
THR215
3.273
HIS218
3.268
GLU219
2.592
HIS222
3.515
Residue
Distance (Å)
HIS228
2.955
PRO232
3.186
LYS233
3.664
ALA234
3.415
VAL235
3.257
PHE237
3.107
PRO238
3.390
THR239
3.172
TYR240
2.919
LYS241
3.500
VAL243
3.421
PHE248
3.247
ARG249
4.756
References  Top
REF 1 Molecular determinants of a selective matrix metalloprotease-12 inhibitor: insights from crystallography and thermodynamic studies. J Med Chem. 2013 Feb 14;56(3):1149-59.
REF 2 Zinc-Metalloproteinase Inhibitors: Evaluation of the Complex Role Played by the Zinc-Binding Group on Potency and Selectivity. J Med Chem. 2017 Jan 12;60(1):403-414.
REF 3 Synthesis and in Vitro and in Vivo Evaluation of MMP-12 Selective Optical Probes. Bioconjug Chem. 2016 Oct 19;27(10):2407-2417.

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