2vo5

From Proteopedia

(Difference between revisions)

Revision as of 06:31, 24 April 2008

STRUCTURAL AND BIOCHEMICAL EVIDENCE FOR A BOAT-LIKE TRANSITION STATE IN BETA-MANNOSIDASES

Overview

Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on alpha- or beta-mannosides harness unusual B2,5 (boat) transition states. Here we present the analysis of 25 putative beta-mannosidase inhibitors, whose Ki values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron beta-mannosidase BtMan2A. B2,5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log Ki with log Km/kcat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B2,5 transition state during enzymatic beta-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining alpha-mannosidases--an area that is emerging for anticancer therapeutics.

About this Structure

2VO5 is a Single protein structure of sequence from Bacteroides thetaiotaomicron. Full crystallographic information is available from OCA.

Reference

Structural and biochemical evidence for a boat-like transition state in beta-mannosidases., Tailford LE, Offen WA, Smith NL, Dumon C, Morland C, Gratien J, Heck MP, Stick RV, Bleriot Y, Vasella A, Gilbert HJ, Davies GJ, Nat Chem Biol. 2008 May;4(5):306-12. PMID:18408714 Page seeded by OCA on Thu Apr 24 09:31:06 2008

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OCA

Retrieved from "http://52.214.119.220/wiki/index.php/2vo5"

@@ Line 1: / Line 1: @@
 [[Image:2vo5.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 2vo5 |SIZE=350|CAPTION= <scene name='initialview01'>2vo5</scene>, resolution 2.30&Aring;
+The line below this paragraph, containing "STRUCTURE_2vo5", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=AC1:Binding+Site+For+Residue+Vbz+A+1865'>AC1</scene>, <scene name='pdbsite=AC2:Binding+Site+For+Residue+Vbz+B+1868'>AC2</scene>, <scene name='pdbsite=AC3:Binding+Site+For+Residue+Edo+B+1869'>AC3</scene>, <scene name='pdbsite=AC4:Binding+Site+For+Residue+Edo+A+1866'>AC4</scene>, <scene name='pdbsite=AC5:Binding+Site+For+Residue+Edo+A+1867'>AC5</scene>, <scene name='pdbsite=AC6:Binding+Site+For+Residue+Edo+B+1870'>AC6</scene>, <scene name='pdbsite=AC7:Binding+Site+For+Residue+Edo+A+1868'>AC7</scene>, <scene name='pdbsite=AC8:Binding+Site+For+Residue+Edo+B+1871'>AC8</scene>, <scene name='pdbsite=AC9:Binding+Site+For+Residue+Edo+B+1872'>AC9</scene>, <scene name='pdbsite=BC1:Binding+Site+For+Residue+Edo+B+1873'>BC1</scene>, <scene name='pdbsite=BC2:Binding+Site+For+Residue+Edo+B+1874'>BC2</scene>, <scene name='pdbsite=BC3:Binding+Site+For+Residue+Edo+A+1869'>BC3</scene>, <scene name='pdbsite=BC4:Binding+Site+For+Residue+Edo+B+1875'>BC4</scene>, <scene name='pdbsite=BC5:Binding+Site+For+Residue+Edo+A+1870'>BC5</scene>, <scene name='pdbsite=BC6:Binding+Site+For+Residue+Edo+B+1876'>BC6</scene>, <scene name='pdbsite=BC7:Binding+Site+For+Residue+Edo+A+1871'>BC7</scene>, <scene name='pdbsite=BC8:Binding+Site+For+Residue+Edo+B+1877'>BC8</scene>, <scene name='pdbsite=BC9:Binding+Site+For+Residue+Edo+B+1878'>BC9</scene>, <scene name='pdbsite=CC1:Binding+Site+For+Residue+Edo+B+1879'>CC1</scene>, <scene name='pdbsite=CC2:Binding+Site+For+Residue+Edo+B+1880'>CC2</scene>, <scene name='pdbsite=CC3:Binding+Site+For+Residue+Edo+B+1881'>CC3</scene>, <scene name='pdbsite=CC4:Binding+Site+For+Residue+Edo+B+1882'>CC4</scene>, <scene name='pdbsite=CC5:Binding+Site+For+Residue+Edo+A+1872'>CC5</scene>, <scene name='pdbsite=CC6:Binding+Site+For+Residue+Edo+B+1883'>CC6</scene>, <scene name='pdbsite=CC7:Binding+Site+For+Residue+Edo+A+1873'>CC7</scene>, <scene name='pdbsite=CC8:Binding+Site+For+Residue+Br+A+1874'>CC8</scene>, <scene name='pdbsite=CC9:Binding+Site+For+Residue+Br+B+1884'>CC9</scene>, <scene name='pdbsite=DC1:Binding+Site+For+Residue+Br+B+1885'>DC1</scene>, <scene name='pdbsite=DC2:Binding+Site+For+Residue+Cl+A+1876'>DC2</scene>, <scene name='pdbsite=DC3:Binding+Site+For+Residue+Cl+B+1887'>DC3</scene>, <scene name='pdbsite=DC4:Binding+Site+For+Residue+Cl+A+1877'>DC4</scene>, <scene name='pdbsite=DC5:Binding+Site+For+Residue+Cl+B+1888'>DC5</scene>, <scene name='pdbsite=DC6:Binding+Site+For+Residue+Edo+A+1878'>DC6</scene>, <scene name='pdbsite=DC7:Binding+Site+For+Residue+Edo+B+1889'>DC7</scene>, <scene name='pdbsite=DC8:Binding+Site+For+Residue+Edo+A+1879'>DC8</scene>, <scene name='pdbsite=DC9:Binding+Site+For+Residue+Edo+B+1890'>DC9</scene>, <scene name='pdbsite=EC1:Binding+Site+For+Residue+Edo+B+1891'>EC1</scene>, <scene name='pdbsite=EC2:Binding+Site+For+Residue+Edo+B+1892'>EC2</scene>, <scene name='pdbsite=EC3:Binding+Site+For+Residue+Edo+A+1880'>EC3</scene>, <scene name='pdbsite=EC4:Binding+Site+For+Residue+Edo+A+1881'>EC4</scene>, <scene name='pdbsite=EC5:Binding+Site+For+Residue+Br+B+1893'>EC5</scene>, <scene name='pdbsite=EC6:Binding+Site+For+Residue+Edo+A+1883'>EC6</scene> and <scene name='pdbsite=EC7:Binding+Site+For+Residue+Edo+A+1885'>EC7</scene>
+You may change the PDB parameter (which sets the PDB file loaded into the applet)
-|LIGAND= <scene name='pdbligand=BR:BROMIDE+ION'>BR</scene>, <scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=VBZ:(1R,4R,5R,7R,8R)-2-BENZYL-5-HYDROXYMETHYL-2-AZA-BICYCLO[2.2.2]OCTANE-4,7,8-TRIOL'>VBZ</scene>
+or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
-|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-mannosidase Beta-mannosidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.25 3.2.1.25] </span>
+or leave the SCENE parameter empty for the default display.
-|GENE=
+-->
-|DOMAIN=<span class='plainlinks'>[http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=pfam02837 Glyco_hydro_2_N], [http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=COG3250 LacZ], [http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=pfam02836 Glyco_hydro_2_C]</span>
+{{STRUCTURE_2vo5|  PDB=2vo5  |  SCENE=  }}
-|RELATEDENTRY=[[2vqt|2VQT]], [[2vot|2VOT]], [[2vl4|2VL4]], [[2vqu|2VQU]], [[2vo5|2VO5]], [[2je8|2JE8]], [[2vjx|2VJX]], [[2vmf|2VMF]]
-|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2vo5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vo5 OCA], [http://www.ebi.ac.uk/pdbsum/2vo5 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2vo5 RCSB]</span>
-}}
 '''STRUCTURAL AND BIOCHEMICAL EVIDENCE FOR A BOAT-LIKE TRANSITION STATE IN BETA-MANNOSIDASES'''
+==Overview==
+Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on alpha- or beta-mannosides harness unusual B2,5 (boat) transition states. Here we present the analysis of 25 putative beta-mannosidase inhibitors, whose Ki values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron beta-mannosidase BtMan2A. B2,5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log Ki with log Km/kcat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B2,5 transition state during enzymatic beta-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining alpha-mannosidases--an area that is emerging for anticancer therapeutics.
 ==About this Structure==
 VO5 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Bacteroides_thetaiotaomicron Bacteroides thetaiotaomicron]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2VO5 OCA].
+==Reference==
+Structural and biochemical evidence for a boat-like transition state in beta-mannosidases., Tailford LE, Offen WA, Smith NL, Dumon C, Morland C, Gratien J, Heck MP, Stick RV, Bleriot Y, Vasella A, Gilbert HJ, Davies GJ, Nat Chem Biol. 2008 May;4(5):306-12. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/18408714 18408714]
 [[Category: Bacteroides thetaiotaomicron]]
 [[Category: Beta-mannosidase]]
@@ Line 28: / Line 31: @@
 [[Category: Moreland, C.]]
 [[Category: Offen, W A.]]
-[[Category: Smith, N.]]
+[[Category: Smith, N L.]]
 [[Category: Stick, R V.]]
-[[Category: Tailford, L N.]]
+[[Category: Tailford, L E.]]
 [[Category: Vasella, A.]]
-[[Category: glycoside]]
+[[Category: Glycoside]]
-[[Category: hydrolase,mannosidase,transition state mimic]]
+[[Category: Hydrolase]]
-[[Category: linear free energy relationship]]
+[[Category: Linear free energy relationship]]
+[[Category: Mannosidase]]
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr  2 11:58:41 2008''
+[[Category: Transition state mimic]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Apr 24 09:31:06 2008''

2vo5

From Proteopedia

Revision as of 06:31, 24 April 2008

Overview

About this Structure

Reference

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