2obf

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[[Image:2obf.jpg|left|200px]]
[[Image:2obf.jpg|left|200px]]
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{{Structure
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<!--
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|PDB= 2obf |SIZE=350|CAPTION= <scene name='initialview01'>2obf</scene>, resolution 2.300&Aring;
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The line below this paragraph, containing "STRUCTURE_2obf", creates the "Structure Box" on the page.
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|SITE=
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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|LIGAND= <scene name='pdbligand=F83:(3R)-N-(4-CHLOROPHENYL)-3-(HYDROXYMETHYL)-1,2,3,4-TETRAHYDROISOQUINOLINE-7-SULFONAMIDE'>F83</scene>, <scene name='pdbligand=SAH:S-ADENOSYL-L-HOMOCYSTEINE'>SAH</scene>
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Phenylethanolamine_N-methyltransferase Phenylethanolamine N-methyltransferase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.28 2.1.1.28] </span>
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or leave the SCENE parameter empty for the default display.
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|GENE=
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|DOMAIN=
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{{STRUCTURE_2obf| PDB=2obf | SCENE= }}
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|RELATEDENTRY=[[2g8n|2G8N]], [[1hnn|1HNN]]
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|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2obf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2obf OCA], [http://www.ebi.ac.uk/pdbsum/2obf PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2obf RCSB]</span>
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}}
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'''Structure of K57A hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy (SAH)'''
'''Structure of K57A hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy (SAH)'''
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[[Category: Drinkwater, N.]]
[[Category: Drinkwater, N.]]
[[Category: Martin, J L.]]
[[Category: Martin, J L.]]
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[[Category: methyltransferase]]
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[[Category: Methyltransferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 10:33:21 2008''
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 04:15:24 2008''
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Revision as of 07:33, 4 May 2008

Image:2obf.jpg

Template:STRUCTURE 2obf

Structure of K57A hPNMT with inhibitor 3-Hydroxymethyl-7-(N-4-chlorophenylaminosulfonyl)-THIQ and AdoHcy (SAH)


Overview

Shape complementarity is a fundamental principle of inhibitor design. Here we show that an enzyme for which the crystal structure has been determined (phenylethanolamine N-methyltransferase, PNMT) conceals a cryptic binding site. This site is revealed upon binding of inhibitors that are double the size of the physiological substrate. These large inhibitors are not predicted to bind in that they protrude through the accessible surface calculated from a PNMT/7-aminosulfonyl-1,2,3,4-tetrahydroisoquinoline (SK&F 29661) crystal structure, yet they are potent inhibitors of PNMT. We determined structures of the enzyme complexed with large inhibitors and found that the volume of the active site increases by 140 A3 upon binding. Changes in active site size and shape are brought about by unfavorable side chain conformations and rigid body helix motions. The energetic cost is modest, estimated at 2-3 kcal/mol from mutational analyses. Our findings further underline the importance of protein flexibility in structure-based inhibitor design studies.

About this Structure

2OBF is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.

Reference

Enzyme adaptation to inhibitor binding: a cryptic binding site in phenylethanolamine N-methyltransferase., Gee CL, Drinkwater N, Tyndall JD, Grunewald GL, Wu Q, McLeish MJ, Martin JL, J Med Chem. 2007 Oct 4;50(20):4845-53. Epub 2007 Sep 11. PMID:17845018 Page seeded by OCA on Sun May 4 10:33:21 2008

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