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PDBsum entry 2vmf

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protein ligands metals Protein-protein interface(s) links
Hydrolase PDB id
2vmf
Jmol
Contents
Protein chains
835 a.a. *
Ligands
MVL ×2
EDO ×40
Metals
_BR ×16
_CL ×11
Waters ×949
* Residue conservation analysis
PDB id:
2vmf
Name: Hydrolase
Title: Structural and biochemical evidence for a boat-like transition state in beta-mannosidases
Structure: Beta-mannosidase. Chain: a, b. Fragment: residues 26-864. Engineered: yes. Other_details: c-terminal his-tagged beta-mannosidase
Source: Bacteroides thetaiotaomicron. Organism_taxid: 226186. Strain: vpi-5482. Atcc: 29148. Expressed in: escherichia coli. Expression_system_taxid: 511693.
Resolution:
2.10Å     R-factor:   0.167     R-free:   0.223
Authors: L.E.Tailford,W.A.Offen,N.L.Smith,C.Dumon,C.Moreland, J.Gratien,M.P.Heck,R.V.Stick,Y.Bleriot,A.Vasella, H.J.Gilbert,G.J.Davies
Key ref:
L.E.Tailford et al. (2008). Structural and biochemical evidence for a boat-like transition state in beta-mannosidases. Nat Chem Biol, 4, 306-312. PubMed id: 18408714 DOI: 10.1038/nchembio.81
Date:
25-Jan-08     Release date:   01-Apr-08    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
Q8AAK6  (Q8AAK6_BACTN) -  Beta-mannosidase
Seq:
Struc:
 
Seq:
Struc:
864 a.a.
835 a.a.
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     carbohydrate metabolic process   2 terms 
  Biochemical function     hydrolase activity, hydrolyzing O-glycosyl compounds     2 terms  

 

 
DOI no: 10.1038/nchembio.81 Nat Chem Biol 4:306-312 (2008)
PubMed id: 18408714  
 
 
Structural and biochemical evidence for a boat-like transition state in beta-mannosidases.
L.E.Tailford, W.A.Offen, N.L.Smith, C.Dumon, C.Morland, J.Gratien, M.P.Heck, R.V.Stick, Y.Blériot, A.Vasella, H.J.Gilbert, G.J.Davies.
 
  ABSTRACT  
 
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.
 
  Selected figure(s)  
 
Figure 3.
Residues selected for site-directed mutants (Q646A, Y537A, N461A, W198G, W395A and W645A) and the catalytic acid/base and nucleophile (Glu462 and Glu555, respectively) are shown. Also shown are the interactions of the +1 subsite, notably Trp217, Trp533 and Tyr537, which enrobe the hydrophobic groups of 1c. The figure is in divergent stereo with the 2F[o] – F[c] map shown at 1 .
Figure 4.
The 2F[o] – F[c] map is shown at 1 . Also shown is the complex of 5 with the W645A mutant and the overlap of the wild-type (gray) and W645A (yellow) complexes with 5.
 
  The above figures are reprinted by permission from Macmillan Publishers Ltd: Nat Chem Biol (2008, 4, 306-312) copyright 2008.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
20689974 Y.He, A.K.Bubb, K.A.Stubbs, T.M.Gloster, and G.J.Davies (2011).
Inhibition of a bacterial O-GlcNAcase homologue by lactone and lactam derivatives: structural, kinetic and thermodynamic analyses.
  Amino Acids, 40, 829-839.
PDB codes: 2xm1 2xm2
19940122 A.I.Guce, N.E.Clark, E.N.Salgado, D.R.Ivanen, A.A.Kulminskaya, H.Brumer, and S.C.Garman (2010).
Catalytic mechanism of human alpha-galactosidase.
  J Biol Chem, 285, 3625-3632.
PDB codes: 3hg2 3hg3 3hg4 3hg5
20140249 M.D.Suits, Y.Zhu, E.J.Taylor, J.Walton, D.L.Zechel, H.J.Gilbert, and G.J.Davies (2010).
Structure and kinetic investigation of Streptococcus pyogenes family GH38 alpha-mannosidase.
  PLoS One, 5, e9006.
PDB codes: 2wyh 2wyi
20396401 T.M.Gloster, and D.J.Vocadlo (2010).
Mechanism, Structure, and Inhibition of O-GlcNAc Processing Enzymes.
  Curr Signal Transduct Ther, 5, 74-91.  
20066263 T.M.Gloster, and G.J.Davies (2010).
Glycosidase inhibition: assessing mimicry of the transition state.
  Org Biomol Chem, 8, 305-320.  
20081828 Y.Zhu, M.D.Suits, A.J.Thompson, S.Chavan, Z.Dinev, C.Dumon, N.Smith, K.W.Moremen, Y.Xiang, A.Siriwardena, S.J.Williams, H.J.Gilbert, and G.J.Davies (2010).
Mechanistic insights into a Ca2+-dependent family of alpha-mannosidases in a human gut symbiont.
  Nat Chem Biol, 6, 125-132.
PDB codes: 2wvx 2wvy 2wvz 2ww0 2ww1 2ww2 2ww3 2wzs
19437524 B.Brumshtein, M.Aguilar-Moncayo, M.I.García-Moreno, C.Ortiz Mellet, J.M.García Fernández, I.Silman, Y.Shaaltiel, D.Aviezer, J.L.Sussman, and A.H.Futerman (2009).
6-Amino-6-deoxy-5,6-di-N-(N'-octyliminomethylidene)nojirimycin: synthesis, biological evaluation, and crystal structure in complex with acid beta-glucosidase.
  Chembiochem, 10, 1480-1485.
PDB code: 2wcg
19532990 M.Aguilar-Moncayo, T.M.Gloster, J.P.Turkenburg, M.I.García-Moreno, C.Ortiz Mellet, G.J.Davies, and J.M.García Fernández (2009).
Glycosidase inhibition by ring-modified castanospermine analogues: tackling enzyme selectivity by inhibitor tailoring.
  Org Biomol Chem, 7, 2738-2747.
PDB codes: 2wbg 2wc3 2wc4
18799462 A.Cartmell, E.Topakas, V.M.Ducros, M.D.Suits, G.J.Davies, and H.J.Gilbert (2008).
The Cellvibrio japonicus mannanase CjMan26C displays a unique exo-mode of action that is conferred by subtle changes to the distal region of the active site.
  J Biol Chem, 283, 34403-34413.
PDB codes: 2vx4 2vx5 2vx6 2vx7
18822375 B.Henrissat, G.Sulzenbacher, and Y.Bourne (2008).
Glycosyltransferases, glycoside hydrolases: surprise, surprise!
  Curr Opin Struct Biol, 18, 527-533.  
18558099 D.J.Vocadlo, and G.J.Davies (2008).
Mechanistic insights into glycosidase chemistry.
  Curr Opin Chem Biol, 12, 539-555.  
18421285 M.M.Palcic (2008).
Beta-mannoside hydrolysis goes by boat.
  Nat Chem Biol, 4, 269-270.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.