Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T47466 | Target Info | |||
| Target Name | Porphobilinogen deaminase (HMBS) | ||||
| Synonyms | Preuroporphyrinogen synthase; PBGD; Hydroxymethylbilane synthase; HMBS | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | HMBS | ||||
| Biochemical Class | Alkyl aryl transferase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | 3-[5-{[3-(2-Carboxyethyl)-4-(Carboxymethyl)-5-Methyl-1h-Pyrrol-2-Yl]methyl}-4-(Carboxymethyl)-1h-Pyrrol-3-Yl]propanoic Acid | Ligand Info | |||
| Canonical SMILES | CC1=C(C(=C(N1)CC2=C(C(=CN2)CCC(=O)O)CC(=O)O)CCC(=O)O)CC(=O)O | ||||
| InChI | 1S/C20H24N2O8/c1-10-13(6-19(27)28)12(3-5-18(25)26)16(22-10)8-15-14(7-20(29)30)11(9-21-15)2-4-17(23)24/h9,21-22H,2-8H2,1H3,(H,23,24)(H,25,26)(H,27,28)(H,29,30) | ||||
| InChIKey | LCAXMKQKEYTFDM-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 5460481 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 7CCX Crystal structure of the holo form of human hydroxymethylbilane synthase | ||||||
| Method | X-ray diffraction | Resolution | 1.84 Å | Mutation | No | [1] |
| PDB Sequence |
MRVIRVGTRK
27 SQLARIQTDS37 VVATLKASYP47 GLQFEIIAMS57 FTKELEHALE86 KNEVDLVVHS 96 LKDLPTVLPP106 GFTIGAICKR116 ENPHDAVVFH126 PKFVGKTLET136 LPEKSVVGTS 146 SLRRAAQLQR156 KFPHLEFRSI166 RGNLNTRLRK176 LDEQQEFSAI186 ILATAGLQRM 196 GWHNRVGQIL206 HPEECMYAVG216 QGALGVEVRA226 KDQDILDLVG236 VLHDPETLLR 246 CIAERAFLRH256 LEGGCSVPVA266 VHTAMKDGQL276 YLTGGVWSLD286 GSDSIQETMQ 296 ATIHVPAQHE306 DGPEDDPQLV316 GITARNIPRG326 PQLAAQNLGI336 SLANLLLSKG 346 AKNILDVA
|
|||||
|
|
LEU30
4.293
GLN34
4.260
SER96
2.847
LYS98
2.608
ASP99
2.910
THR145
4.591
SER146
3.129
SER147
2.661
ARG149
2.726
ARG150
2.709
ILE166
4.779
LEU170
4.629
ARG173
2.994
|
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| PDB ID: 7CCY Crystal structure of the 2-iodoporphobilinogen-bound holo form of human hydroxymethylbilane synthase | ||||||
| Method | X-ray diffraction | Resolution | 2.40 Å | Mutation | No | [1] |
| PDB Sequence |
RVIRVGTRKS
28 QLARIQTDSV38 VATLKASYPG48 LQFEIIAMST58 TGDKELEHAL85 EKNEVDLVVH 95 SLKDLPTVLP105 PGFTIGAICK115 RENPHDAVVF125 HPKFVGKTLE135 TLPEKSVVGT 145 SSLRRAAQLQ155 RKFPHLEFRS165 IRGNLNTRLR175 KLDEQQEFSA185 IILATAGLQR 195 MGWHNRVGQI205 LHPEECMYAV215 GQGALGVEVR225 AKDQDILDLV235 GVLHDPETLL 245 RCIAERAFLR255 HLEGGCSVPV265 AVHTAMKDGQ275 LYLTGGVWSL285 DGSDSIQETM 295 QATIHVPAQH305 EDGPEDDPQL315 VGITARNIPR325 GPQLAAQNLG335 ISLANLLLSK 345 GAKNILDVA
|
|||||
|
|
LEU30
4.026
GLN34
3.973
SER96
2.830
LYS98
2.506
ASP99
2.896
THR145
4.429
SER146
3.137
SER147
2.827
ARG149
2.662
ARG150
2.503
ILE166
4.749
LEU170
4.333
ARG173
2.896
|
|||||
| PDB ID: 3EQ1 The Crystal Structure of Human Porphobilinogen Deaminase at 2.8A resolution | ||||||
| Method | X-ray diffraction | Resolution | 2.80 Å | Mutation | Yes | [2] |
| PDB Sequence |
RVIRVGTRKS
28 QLARIQTDSV38 VATLKASYPG48 LQFEIIAFTK79 ELEHALEKNE89 VDLVVHSLKD 99 LPTVLPPGFT109 IGAICKRENP119 HDAVVFHPKF129 VGKTLETLPE139 KSVVGTSSLR 149 RAAQLQRKFP159 HLEFRSIQGN169 LNTRLRKLDE179 QQEFSAIILA189 TAGLQRMGWH 199 NRVGQILHPE209 ECMYAVGQGA219 LGVEVRAKDQ229 DILDLVGVLH239 DPETLLRCIA 249 ERAFLRHLEG259 GCSVPVAVHT269 AMKDGQLYLT279 GGVWSLDGSD289 SIQETMQATI 299 HVPQHEDDPQ314 LVGITARNIP324 RGPQLAAQNL334 GISLANLLLS344 KGAKNILDVA 354 RQ
|
|||||
|
|
LEU30
4.681
GLN34
4.342
SER96
2.698
LYS98
2.537
ASP99
3.126
THR145
3.819
SER146
2.827
SER147
3.045
ARG149
2.455
ARG150
2.759
ARG173
2.787
ILE187
4.432
|
|||||
| PDB ID: 7AAJ Human porphobilinogen deaminase in complex with cofactor | ||||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | No | [3] |
| PDB Sequence |
KMRVIRVGTR
26 KSQLARIQTD36 SVVATLKASY46 PGLQFEIIAM56 SSLFTKELEH83 ALEKNEVDLV 93 VHSLKDLPTV103 LPPGFTIGAI113 CKRENPHDAV123 VFHPKFVGKT133 LETLPEKSVV 143 GTSSLRRAAQ153 LQRKFPHLEF163 RSIRGNLNTR173 LRKLDEQQEF183 SAIILATAGL 193 QRMGWHNRVG203 QILHPEECMY213 AVGQGALGVE223 VRAKDQDILD233 LVGVLHDPET 243 LLRCIAERAF253 LRHLEGGCSV263 PVAVHTAMKD273 GQLYLTGGVW283 SLDGSDSIQE 293 TMQATIHVPA303 QHEDGPEDDP313 QLVGITARNI323 PRGPQLAAQN333 LGISLANLLL 343 SKGAKNILDV353 ARQL
|
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|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .DPM or .DPM2 or .DPM3 or :3DPM;style chemicals stick;color identity;select .B:30 or .B:34 or .B:96 or .B:98 or .B:99 or .B:145 or .B:146 or .B:147 or .B:149 or .B:150 or .B:166 or .B:170 or .B:173 or .B:188 or .B:189 or .B:191 or .B:192 or .B:195 or .B:214 or .B:216 or .B:217 or .B:218 or .B:220 or .B:261; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU30
4.138
GLN34
3.698
SER96
2.747
LYS98
2.665
ASP99
2.999
THR145
3.516
SER146
3.266
SER147
2.821
ARG149
2.666
ARG150
3.057
ILE166
4.221
LEU170
4.240
|
|||||
| PDB ID: 3ECR Structure of human porphobilinogen deaminase | ||||||
| Method | X-ray diffraction | Resolution | 2.18 Å | Mutation | No | [4] |
| PDB Sequence |
MRVIRVGTRK
30 SQLARIQTDS40 VVATLKASYP50 GLQFEIIAML79 FTKELEHALE89 KNEVDLVVHS 99 LKDLPTVLPP109 GFTIGAICKR119 ENPHDAVVFH129 PKFVGKTLET139 LPEKSVVGTS 149 SLRRAAQLQR159 KFPHLEFRSI169 RGNLNTRLRK179 LDEQQEFSAI189 ILATAGLQRM 199 GWHNRVGQIL209 HPEECMYAVG219 QGALGVEVRA229 KDQDILDLVG239 VLHDPETLLR 249 CIAERAFLRH259 LECSVPVAVH271 TAMKDGQLYL281 TGGVWSLDGS291 DSIQETMQAT 301 IHVPAQHEDG311 PEDDPQLVGI321 TARNIPRGPQ331 LAAQNLGISL341 ANLLLSKGAK 351 NILDVARQ
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .DPM or .DPM2 or .DPM3 or :3DPM;style chemicals stick;color identity;select .A:33 or .A:37 or .A:99 or .A:101 or .A:102 or .A:148 or .A:149 or .A:150 or .A:152 or .A:153 or .A:169 or .A:176 or .A:190 or .A:191 or .A:192 or .A:194 or .A:195 or .A:198 or .A:217 or .A:219 or .A:220 or .A:221 or .A:222 or .A:264; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU33
4.436
GLN37
3.857
SER99
3.016
LYS101
2.601
ASP102
2.786
THR148
3.687
SER149
3.441
SER150
2.621
ARG152
2.690
ARG153
2.877
ILE169
4.989
ARG176
2.726
|
|||||
| PDB ID: 5M7F Human porphobilinogen deaminase in complex with DPM cofactor | ||||||
| Method | X-ray diffraction | Resolution | 2.78 Å | Mutation | No | [5] |
| PDB Sequence |
VIRVGTRKSQ
29 LARIQTDSVV39 ATLKASYPGL49 QFEIIAMSSL76 FTKELEHALE86 KNEVDLVVHS 96 LKDLPTVLPP106 GFTIGAICKR116 ENPHDAVVFH126 PKFVGKTLET136 LPEKSVVGTS 146 SLRRAAQLQR156 KFPHLEFRSI166 RGNLNTRLRK176 LDEQQEFSAI186 ILATAGLQRM 196 GWHNRVGQIL206 HPEECMYAVG216 QGALGVEVRA226 KDQDILDLVG236 VLHDPETLLR 246 CIAERAFLRH256 LEGGCSVPVA266 VHTAMKDGQL276 YLTGGVWSLD286 GSDSIQETMQ 296 ATIHVPAQHE306 DGPEDDPQLV316 GITARNIPRG326 PQLAAQNLGI336 SLANLLLSKG 346 AKNILDV
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .DPM or .DPM2 or .DPM3 or :3DPM;style chemicals stick;color identity;select .A:30 or .A:34 or .A:96 or .A:97 or .A:98 or .A:99 or .A:145 or .A:146 or .A:147 or .A:148 or .A:149 or .A:150 or .A:168 or .A:170 or .A:173 or .A:188 or .A:189 or .A:191 or .A:192 or .A:195 or .A:214 or .A:216 or .A:217 or .A:218 or .A:219 or .A:220 or .A:261 or .A:262 or .A:263; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU30
2.913
GLN34
3.209
SER96
2.549
LEU97
4.185
LYS98
2.152
ASP99
1.823
THR145
3.973
SER146
2.666
SER147
2.148
LEU148
4.531
ARG149
1.662
ARG150
2.275
GLY168
4.831
LEU170
3.197
ARG173
2.271
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Crystal structures of hydroxymethylbilane synthase complexed with a substrate analog: a single substrate-binding site for four consecutive condensation steps. Biochem J. 2021 Mar 12;478(5):1023-1042. | ||||
| REF 2 | Structure of human porphobilinogen deaminase at 2.8 A: the molecular basis of acute intermittent porphyria. Biochem J. 2009 Apr 28;420(1):17-25. | ||||
| REF 3 | Characterization of porphobilinogen deaminase mutants reveals that arginine-173 is crucial for polypyrrole elongation mechanism. iScience. 2021 Feb 6;24(3):102152. | ||||
| REF 4 | Structural insight into acute intermittent porphyria. FASEB J. 2009 Feb;23(2):396-404. | ||||
| REF 5 | Structural basis of pyrrole polymerization in human porphobilinogen deaminase. Biochim Biophys Acta Gen Subj. 2018 Sep;1862(9):1948-1955. | ||||
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