7tx2: Difference between revisions
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==Crystal structure of human phenylethanolamine N-methyltransferase (PNMT) in complex with (2S)-2-amino-4-(((5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(4-(7,8-dichloro-1,2,3,4-tetrahydroisoquinolin-4-yl)butyl)amino)butanoic acid== | |||
<StructureSection load='7tx2' size='340' side='right'caption='[[7tx2]], [[Resolution|resolution]] 2.43Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[7tx2]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TX2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TX2 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.43Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=KNX:(2~{S})-4-[[(2~{R},3~{S},4~{R},5~{R})-5-(6-aminopurin-9-yl)-3,4-bis(oxidanyl)oxolan-2-yl]methyl-[4-[(4~{R})-7,8-bis(chloranyl)-1,2,3,4-tetrahydroisoquinolin-4-yl]butyl]amino]-2-azanyl-butanoic+acid'>KNX</scene></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7tx2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7tx2 OCA], [https://pdbe.org/7tx2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7tx2 RCSB], [https://www.ebi.ac.uk/pdbsum/7tx2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7tx2 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/PNMT_HUMAN PNMT_HUMAN] Converts noradrenaline to adrenaline. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Phenylethanolamine N-methyltransferase (PNMT) catalyzes the S-adenosyl-l-methionine (SAM)-dependent methylation of norepinephrine to form epinephrine. Epinephrine is implicated in the regulation of blood pressure, respiration, Alzheimer's disease, and post-traumatic stress disorder (PTSD). Transition-state (TS) analogues bind their target enzymes orders of magnitude more tightly than their substrates. A synthetic strategy for first-generation TS analogues of human PNMT (hPNMT) permitted structural analysis of hPNMT and revealed potential for second-generation inhibitors [Mahmoodi, N.; J. Am. Chem. Soc. 2020, 142, 14222-14233]. A second-generation TS analogue inhibitor of PNMT was designed, synthesized, and characterized to yield a K(i) value of 1.2 nM. PNMT isothermal titration calorimetry (ITC) measurements of inhibitor 4 indicated a negative cooperative binding mechanism driven by large favorable entropic contributions and smaller enthalpic contributions. Cell-based assays with HEK293T cells expressing PNMT revealed a cell permeable, intracellular PNMT inhibitor with an IC(50) value of 81 nM. Structural analysis demonstrated inhibitor 4 filling catalytic site regions to recapitulate both norepinephrine and SAM interactions. Conformation of the second-generation inhibitor in the catalytic site of PNMT improves contacts relative to those from the first-generation inhibitors. Inhibitor 4 demonstrates up to 51,000-fold specificity for PNMT relative to DNA and protein methyltransferases. Inhibitor 4 also exhibits a 12,000-fold specificity for PNMT over the alpha(2)-adrenoceptor. | |||
Cell-Effective Transition-State Analogue of Phenylethanolamine N-Methyltransferase.,Mahmoodi N, Minnow YVT, Harijan RK, Bedard GT, Schramm VL Biochemistry. 2023 Aug 1;62(15):2257-2268. doi: 10.1021/acs.biochem.3c00103. Epub , 2023 Jul 19. PMID:37467463<ref>PMID:37467463</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Almo | <div class="pdbe-citations 7tx2" style="background-color:#fffaf0;"></div> | ||
[[Category: | |||
[[Category: Harijan | ==See Also== | ||
[[Category: | *[[Phenylethanolamine N-methyltransferase|Phenylethanolamine N-methyltransferase]] | ||
[[Category: | == References == | ||
[[Category: | <references/> | ||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Almo SC]] | |||
[[Category: Bonanno JB]] | |||
[[Category: Harijan RK]] | |||
[[Category: Mahmoodi N]] | |||
[[Category: Minnow YVT]] | |||
[[Category: Schramm VL]] | |||
Latest revision as of 14:35, 23 October 2024
Crystal structure of human phenylethanolamine N-methyltransferase (PNMT) in complex with (2S)-2-amino-4-(((5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(4-(7,8-dichloro-1,2,3,4-tetrahydroisoquinolin-4-yl)butyl)amino)butanoic acidCrystal structure of human phenylethanolamine N-methyltransferase (PNMT) in complex with (2S)-2-amino-4-(((5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methyl)(4-(7,8-dichloro-1,2,3,4-tetrahydroisoquinolin-4-yl)butyl)amino)butanoic acid
Structural highlights
FunctionPNMT_HUMAN Converts noradrenaline to adrenaline. Publication Abstract from PubMedPhenylethanolamine N-methyltransferase (PNMT) catalyzes the S-adenosyl-l-methionine (SAM)-dependent methylation of norepinephrine to form epinephrine. Epinephrine is implicated in the regulation of blood pressure, respiration, Alzheimer's disease, and post-traumatic stress disorder (PTSD). Transition-state (TS) analogues bind their target enzymes orders of magnitude more tightly than their substrates. A synthetic strategy for first-generation TS analogues of human PNMT (hPNMT) permitted structural analysis of hPNMT and revealed potential for second-generation inhibitors [Mahmoodi, N.; J. Am. Chem. Soc. 2020, 142, 14222-14233]. A second-generation TS analogue inhibitor of PNMT was designed, synthesized, and characterized to yield a K(i) value of 1.2 nM. PNMT isothermal titration calorimetry (ITC) measurements of inhibitor 4 indicated a negative cooperative binding mechanism driven by large favorable entropic contributions and smaller enthalpic contributions. Cell-based assays with HEK293T cells expressing PNMT revealed a cell permeable, intracellular PNMT inhibitor with an IC(50) value of 81 nM. Structural analysis demonstrated inhibitor 4 filling catalytic site regions to recapitulate both norepinephrine and SAM interactions. Conformation of the second-generation inhibitor in the catalytic site of PNMT improves contacts relative to those from the first-generation inhibitors. Inhibitor 4 demonstrates up to 51,000-fold specificity for PNMT relative to DNA and protein methyltransferases. Inhibitor 4 also exhibits a 12,000-fold specificity for PNMT over the alpha(2)-adrenoceptor. Cell-Effective Transition-State Analogue of Phenylethanolamine N-Methyltransferase.,Mahmoodi N, Minnow YVT, Harijan RK, Bedard GT, Schramm VL Biochemistry. 2023 Aug 1;62(15):2257-2268. doi: 10.1021/acs.biochem.3c00103. Epub , 2023 Jul 19. PMID:37467463[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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