2vl4: Difference between revisions

Revision as of 09:30, 24 April 2008

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

OverviewOverview

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 StructureAbout this Structure

2VL4 is a Single protein structure of sequence from Bacteroides thetaiotaomicron. Full crystallographic information is available from OCA.

ReferenceReference

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 09:30:43 2008

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA

@@ Line 1: / Line 1: @@
 [[Image:2vl4.jpg|left|200px]]
- {{Structure
+<!--
-|PDB= 2vl4 |SIZE=350|CAPTION= <scene name='initialview01'>2vl4</scene>, resolution 1.90&Aring;
+The line below this paragraph, containing "STRUCTURE_2vl4", creates the "Structure Box" on the page.
-|SITE= <scene name='pdbsite=AC1:Noz+Binding+Site+For+Residue+A+1865'>AC1</scene>, <scene name='pdbsite=AC2:Noz+Binding+Site+For+Residue+B+1868'>AC2</scene>, <scene name='pdbsite=AC3:Edo+Binding+Site+For+Residue+A+1866'>AC3</scene>, <scene name='pdbsite=AC4:Edo+Binding+Site+For+Residue+B+1869'>AC4</scene>, <scene name='pdbsite=AC5:Edo+Binding+Site+For+Residue+B+1870'>AC5</scene>, <scene name='pdbsite=AC6:Edo+Binding+Site+For+Residue+B+1871'>AC6</scene>, <scene name='pdbsite=AC7:Edo+Binding+Site+For+Residue+A+1867'>AC7</scene>, <scene name='pdbsite=AC8:Edo+Binding+Site+For+Residue+A+1868'>AC8</scene>, <scene name='pdbsite=AC9:Edo+Binding+Site+For+Residue+B+1873'>AC9</scene>, <scene name='pdbsite=BC1:Edo+Binding+Site+For+Residue+B+1874'>BC1</scene>, <scene name='pdbsite=BC2:Edo+Binding+Site+For+Residue+A+1869'>BC2</scene>, <scene name='pdbsite=BC3:Edo+Binding+Site+For+Residue+B+1875'>BC3</scene>, <scene name='pdbsite=BC4:Edo+Binding+Site+For+Residue+B+1876'>BC4</scene>, <scene name='pdbsite=BC5:Edo+Binding+Site+For+Residue+A+1870'>BC5</scene>, <scene name='pdbsite=BC6:Edo+Binding+Site+For+Residue+A+1871'>BC6</scene>, <scene name='pdbsite=BC7:Edo+Binding+Site+For+Residue+B+1877'>BC7</scene>, <scene name='pdbsite=BC8:Edo+Binding+Site+For+Residue+B+1878'>BC8</scene>, <scene name='pdbsite=BC9:Edo+Binding+Site+For+Residue+A+1872'>BC9</scene>, <scene name='pdbsite=CC1:Edo+Binding+Site+For+Residue+A+1873'>CC1</scene>, <scene name='pdbsite=CC2:Edo+Binding+Site+For+Residue+B+1879'>CC2</scene>, <scene name='pdbsite=CC3:Edo+Binding+Site+For+Residue+B+1880'>CC3</scene>, <scene name='pdbsite=CC4:Edo+Binding+Site+For+Residue+A+1874'>CC4</scene>, <scene name='pdbsite=CC5:Edo+Binding+Site+For+Residue+B+1881'>CC5</scene>, <scene name='pdbsite=CC6:Edo+Binding+Site+For+Residue+B+1882'>CC6</scene>, <scene name='pdbsite=CC7:Edo+Binding+Site+For+Residue+A+1875'>CC7</scene>, <scene name='pdbsite=CC8:Edo+Binding+Site+For+Residue+B+1883'>CC8</scene>, <scene name='pdbsite=CC9:Edo+Binding+Site+For+Residue+A+1876'>CC9</scene>, <scene name='pdbsite=DC1:Edo+Binding+Site+For+Residue+A+1877'>DC1</scene>, <scene name='pdbsite=DC2:Br+Binding+Site+For+Residue+A+1878'>DC2</scene>, <scene name='pdbsite=DC3:Br+Binding+Site+For+Residue+B+1884'>DC3</scene>, <scene name='pdbsite=DC4:Br+Binding+Site+For+Residue+A+1880'>DC4</scene>, <scene name='pdbsite=DC5:Br+Binding+Site+For+Residue+B+1885'>DC5</scene>, <scene name='pdbsite=DC6:Br+Binding+Site+For+Residue+B+1886'>DC6</scene>, <scene name='pdbsite=DC7:Br+Binding+Site+For+Residue+A+1883'>DC7</scene>, <scene name='pdbsite=DC8:Edo+Binding+Site+For+Residue+A+1884'>DC8</scene>, <scene name='pdbsite=DC9:Cl+Binding+Site+For+Residue+A+1889'>DC9</scene>, <scene name='pdbsite=EC1:Edo+Binding+Site+For+Residue+B+1888'>EC1</scene>, <scene name='pdbsite=EC2:Cl+Binding+Site+For+Residue+A+1885'>EC2</scene>, <scene name='pdbsite=EC3:Cl+Binding+Site+For+Residue+B+1889'>EC3</scene>, <scene name='pdbsite=EC4:Edo+Binding+Site+For+Residue+B+1890'>EC4</scene>, <scene name='pdbsite=EC5:Br+Binding+Site+For+Residue+A+1886'>EC5</scene>, <scene name='pdbsite=EC6:Edo+Binding+Site+For+Residue+A+1887'>EC6</scene>, <scene name='pdbsite=EC7:Edo+Binding+Site+For+Residue+B+1891'>EC7</scene>, <scene name='pdbsite=EC8:Edo+Binding+Site+For+Residue+B+1893'>EC8</scene>, <scene name='pdbsite=EC9:Cl+Binding+Site+For+Residue+B+1894'>EC9</scene>, <scene name='pdbsite=FC1:Edo+Binding+Site+For+Residue+A+1888'>FC1</scene>, <scene name='pdbsite=FC2:Edo+Binding+Site+For+Residue+B+1895'>FC2</scene> and <scene name='pdbsite=FC3:Cl+Binding+Site+For+Residue+B+1896'>FC3</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=NOZ:(2S,3S,4R,5R)-5-(HYDROXYMETHYL)PIPERIDINE-2,3,4-TRIOL'>NOZ</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_2vl4|  PDB=2vl4  |  SCENE=  }}
-|RELATEDENTRY=[[2vqt|2VQT]], [[2vot|2VOT]], [[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=2vl4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2vl4 OCA], [http://www.ebi.ac.uk/pdbsum/2vl4 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=2vl4 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==
 VL4 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=2VL4 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 hydrolase]]
+[[Category: Glycoside hydrolase]]
-[[Category: hydrolase]]
+[[Category: Hydrolase]]
-[[Category: linear free energy relationship]]
+[[Category: Linear free energy relationship]]
-[[Category: mannosidase]]
+[[Category: Mannosidase]]
-[[Category: transition state mimic]]
+[[Category: Transition state mimic]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Apr 24 09:30:43 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Apr  2 11:58:38 2008''