Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T76213 | Target Info | |||
| Target Name | Phenylalanine hydroxylase (PAH) | ||||
| Synonyms | Phenylalanine4hydroxylase; Phenylalanine-4-hydroxylase; Phe4monooxygenase; Phe-4-monooxygenase | ||||
| Target Type | Successful Target | ||||
| Gene Name | PAH | ||||
| Biochemical Class | Paired donor oxygen oxidoreductase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | BH4 | Ligand Info | |||
| Canonical SMILES | CC(C(C1CNC2=C(N1)C(=O)NC(=N2)N)O)O | ||||
| InChI | 1S/C9H15N5O3/c1-3(15)6(16)4-2-11-7-5(12-4)8(17)14-9(10)13-7/h3-4,6,12,15-16H,2H2,1H3,(H4,10,11,13,14,17)/t3-,4+,6-/m0/s1 | ||||
| InChIKey | FNKQXYHWGSIFBK-RPDRRWSUSA-N | ||||
| PubChem Compound ID | 135398654 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 6HYC The structure of full-length human phenylalanine hydroxylase in complex with the cofactor and negative regulator tetrahydrobiopterin | ||||||
| Method | X-ray diffraction | Resolution | 3.18 Å | Mutation | No | [1] |
| PDB Sequence |
TSYIEDNCNQ
31 NGAISLIFSL41 KEEVGALAKV51 LRLFEENDVN61 LTHIESRPSR71 LKKDEYEFFT 81 HLDKRSLPAL91 TNIIKILRHD101 IGATVHELSR111 DKKKDTVPWF121 PRTIQELDRF 131 ANQILDADHP147 GFKDPVYRAR157 RKQFADIAYN167 YRHGQPIPRV177 EYMEEEKKTW 187 GTVFKTLKSL197 YKTHACYEYN207 HIFPLLEKYC217 GFHEDNIPQL227 EDVSQFLQTC 237 TGFRLRPVAG247 LLSSRDFLGG257 LAFRVFHCTQ267 YIRHGSKPMY277 TPEPDICHEL 287 LGHVPLFSDR297 SFAQFSQEIG307 LASLGAPDEY317 IEKLATIYWF327 TVEFGLCKQG 337 DSIKAYGAGL347 LSSFGELQYC357 LSEKPKLLPL367 ELEKTAIQNY377 TVTEFQPLYY 387 VAESFNDAKE397 KVRNFAATIP407 RPFSVRYDPY417 TQRIEVLDNT427 QQLKILADSI 437 NSEIGILCSA447 LQK
|
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|
|
SER23
3.048
TYR24
4.516
ILE25
4.472
VAL245
3.878
GLY247
2.591
LEU248
3.126
LEU249
2.841
SER250
4.958
SER251
2.455
PHE254
3.100
LEU255
3.237
|
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| PDB ID: 1J8U Catalytic Domain of Human Phenylalanine Hydroxylase Fe(II) in Complex with Tetrahydrobiopterin | ||||||
| Method | X-ray diffraction | Resolution | 1.50 Å | Mutation | No | [2] |
| PDB Sequence |
VPWFPRTIQE
127 LDRFANQILS137 YGAELDADHP147 GFKDPVYRAR157 RKQFADIAYN167 YRHGQPIPRV 177 EYMEEEKKTW187 GTVFKTLKSL197 YKTHACYEYN207 HIFPLLEKYC217 GFHEDNIPQL 227 EDVSQFLQTC237 TGFRLRPVAG247 LLSSRDFLGG257 LAFRVFHCTQ267 YIRHGSKPMY 277 TPEPDICHEL287 LGHVPLFSDR297 SFAQFSQEIG307 LASLGAPDEY317 IEKLATIYWF 327 TVEFGLCKQG337 DSIKAYGAGL347 LSSFGELQYC357 LSEKPKLLPL367 ELEKTAIQNY 377 TVTEFQPLYY387 VAESFNDAKE397 KVRNFAATIP407 RPFSVRYDPY417 TQRIEVL |
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|
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| PDB ID: 1MMK Crystal structure of ternary complex of the catalytic domain of human phenylalanine hydroxylase ((FeII)) complexed with tetrahydrobiopterin and thienylalanine | ||||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [3] |
| PDB Sequence |
TVPWFPRTIQ
126 ELDRFANQIL136 SYGAELDADH146 PGFKDPVYRA156 RRKQFADIAY166 NYRHGQPIPR 176 VEYMEEEKKT186 WGTVFKTLKS196 LYKTHACYEY206 NHIFPLLEKY216 CGFHEDNIPQ 226 LEDVSQFLQT236 CTGFRLRPVA246 GLLSSRDFLG256 GLAFRVFHCT266 QYIRHGSKPM 276 YTPEPDICHE286 LLGHVPLFSD296 RSFAQFSQEI306 GLASLGAPDE316 YIEKLATIYW 326 FTVEFGLCKQ336 GDSIKAYGAG346 LLSSFGELQY356 CLSEKPKLLP366 LELEKTAIQN 376 YTVTEFQPLY386 YVAESFNDAK396 EKVRNFAATI406 PRPFSVRYDP416 YTQRIEVLD |
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|
|
TYR138
3.775
VAL245
3.333
GLY247
3.241
LEU248
3.458
LEU249
2.958
SER250
4.398
SER251
2.782
PHE254
3.601
LEU255
3.993
PHE263
4.235
HIS264
3.498
|
|||||
| PDB ID: 1MMT Crystal structure of ternary complex of the catalytic domain of human phenylalanine hydroxylase (Fe(II)) complexed with tetrahydrobiopterin and norleucine | ||||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [3] |
| PDB Sequence |
TVPWFPRTIQ
126 ELDRFANQIL136 SYGAELDADH146 PGFKDPVYRA156 RRKQFADIAY166 NYRHGQPIPR 176 VEYMEEEKKT186 WGTVFKTLKS196 LYKTHACYEY206 NHIFPLLEKY216 CGFHEDNIPQ 226 LEDVSQFLQT236 CTGFRLRPVA246 GLLSSRDFLG256 GLAFRVFHCT266 QYIRHGSKPM 276 YTPEPDICHE286 LLGHVPLFSD296 RSFAQFSQEI306 GLASLGAPDE316 YIEKLATIYW 326 FTVEFGLCKQ336 GDSIKAYGAG346 LLSSFGELQY356 CLSEKPKLLP366 LELEKTAIQN 376 YTVTEFQPLY386 YVAESFNDAK396 EKVRNFAATI406 PRPFSVRYDP416 YTQRIEVL |
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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 .H4B or .H4B2 or .H4B3 or :3H4B;style chemicals stick;color identity;select .A:138 or .A:245 or .A:247 or .A:248 or .A:249 or .A:250 or .A:251 or .A:254 or .A:255 or .A:263 or .A:264 or .A:265 or .A:266 or .A:281 or .A:285 or .A:286 or .A:290 or .A:322 or .A:325 or .A:326 or .A:330; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
TYR138
4.005
VAL245
3.196
GLY247
2.922
LEU248
3.347
LEU249
2.880
SER250
4.364
SER251
2.738
PHE254
3.452
LEU255
3.823
PHE263
3.936
HIS264
3.451
|
|||||
| PDB ID: 1KW0 Catalytic Domain of Human Phenylalanine Hydroxylase (Fe(II)) in Complex with Tetrahydrobiopterin and Thienylalanine | ||||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [4] |
| PDB Sequence |
VPWFPRTIQE
127 LDRFANQILS137 YGAELDADHP147 GFKDPVYRAR157 RKQFADIAYN167 YRHGQPIPRV 177 EYMEEEKKTW187 GTVFKTLKSL197 YKTHACYEYN207 HIFPLLEKYC217 GFHEDNIPQL 227 EDVSQFLQTC237 TGFRLRPVAG247 LLSSRDFLGG257 LAFRVFHCTQ267 YIRHGSKPMY 277 TPEPDICHEL287 LGHVPLFSDR297 SFAQFSQEIG307 LASLGAPDEY317 IEKLATIYWF 327 TVEFGLCKQG337 DSIKAYGAGL347 LSSFGELQYC357 LSEKPKLLPL367 ELEKTAIQNY 377 TVTEFQPLYY387 VAESFNDAKE397 KVRNFAATIP407 RPFSVRYDPY417 TQRIEVL |
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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 .H4B or .H4B2 or .H4B3 or :3H4B;style chemicals stick;color identity;select .A:138 or .A:245 or .A:247 or .A:248 or .A:249 or .A:250 or .A:251 or .A:254 or .A:255 or .A:263 or .A:264 or .A:265 or .A:266 or .A:281 or .A:285 or .A:286 or .A:290 or .A:322 or .A:325 or .A:326 or .A:330; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
TYR138
4.146
VAL245
3.328
GLY247
2.972
LEU248
3.283
LEU249
2.762
SER250
4.508
SER251
2.717
PHE254
3.496
LEU255
3.626
PHE263
3.965
HIS264
3.498
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Structure of full-length human phenylalanine hydroxylase in complex with tetrahydrobiopterin. Proc Natl Acad Sci U S A. 2019 Jun 4;116(23):11229-11234. | ||||
| REF 2 | High resolution crystal structures of the catalytic domain of human phenylalanine hydroxylase in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin. J Mol Biol. 2001 Nov 23;314(2):279-91. | ||||
| REF 3 | 2.0A resolution crystal structures of the ternary complexes of human phenylalanine hydroxylase catalytic domain with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine or L-norleucine: substrate specificity and molecular motions related to substrate binding. J Mol Biol. 2003 Oct 31;333(4):747-57. | ||||
| REF 4 | Crystal structure of the ternary complex of the catalytic domain of human phenylalanine hydroxylase with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine, and its implications for the mechanism of catalysis and substrate activation. J Mol Biol. 2002 Jul 26;320(5):1095-108. | ||||
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