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PDBsum entry 1m4h
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protein ligands Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
1m4h

 

 

 

 

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Contents
Protein chains
391 a.a. *
Ligands
GLU-LEU-ASP-1OL-
VAL-GLU-PHE ×2
Waters ×450
* Residue conservation analysis
PDB id:
1m4h
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of beta-secretase complexed with inhibitor om00-3
Structure: Beta-secretase. Chain: a, b. Fragment: protease domain. Synonym: memapsin-2. Engineered: yes. Inhibitor om00-3. Chain: c, d. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: bace. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Synthetic construct. Organism_taxid: 32630
Biol. unit: Dimer (from PQS)
Resolution:
2.10Å     R-factor:   0.216     R-free:   0.271
Authors: L.Hong,R.T.Turner,G.Koelsch,A.K.Ghosh,J.Tang
Key ref:
L.Hong et al. (2002). Crystal structure of memapsin 2 (beta-secretase) in complex with an inhibitor OM00-3. Biochemistry, 41, 10963-10967. PubMed id: 12206667 DOI: 10.1021/bi026232n
Date:
02-Jul-02     Release date:   28-Aug-02    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P56817  (BACE1_HUMAN) -  Beta-secretase 1 from Homo sapiens
Seq:
Struc: 		501 a.a.
391 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.23.46  - memapsin 2.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
DOI no: 10.1021/bi026232n Biochemistry 41:10963-10967 (2002)
PubMed id: 12206667  
 
 
Crystal structure of memapsin 2 (beta-secretase) in complex with an inhibitor OM00-3.
L.Hong, R.T.Turner, G.Koelsch, D.Shin, A.K.Ghosh, J.Tang.
 
  ABSTRACT  
 
The structure of the catalytic domain of human memapsin 2 bound to an inhibitor OM00-3 (Glu-Leu-Asp-LeuAla-Val-Glu-Phe, K(i) = 0.3 nM, the asterisk denotes the hydroxyethylene transition-state isostere) has been determined at 2.1 A resolution. Uniquely defined in the structure are the locations of S(3)' and S(4)' subsites, which were not identified in the previous structure of memapsin 2 in complex with the inhibitor OM99-2 (Glu-Val-Asn-LeuAla-Ala-Glu-Phe, K(i) = 1 nM). Different binding modes for the P(2) and P(4) side chains are also observed. These new structural elements are useful for the design of new inhibitors. The structural and kinetic data indicate that the replacement of the P(2)' alanine in OM99-2 with a valine in OM00-3 stabilizes the binding of P(3)' and P(4)'.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21244641 G.Chiriano, A.Sartini, F.Mancini, V.Andrisano, M.L.Bolognesi, M.Roberti, M.Recanatini, P.Carloni, and A.Cavalli (2011).
Sequential Virtual Screening Approach to the Identification of Small Organic Molecules as Potential BACE-1 Inhibitors.
  Chem Biol Drug Des, 77, 268-271.  
20731541 D.W.Klaver, M.C.Wilce, H.Cui, A.C.Hung, R.Gasperini, L.Foa, and D.H.Small (2010).
Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions.
  Biol Chem, 391, 849-859.  
20853423 X.Li, H.Bo, X.C.Zhang, J.A.Hartsuck, and J.Tang (2010).
Predicting memapsin 2 (β-secretase) hydrolytic activity.
  Protein Sci, 19, 2175-2185.  
19866487 X.Li, Y.Nakajima, K.Niwa, V.R.Viviani, and Y.Ohmiya (2010).
Enhanced red-emitting railroad worm luciferase for bioassays and bioimaging.
  Protein Sci, 19, 26-33.  
  20661410 X.Luo, and R.Yan (2010).
Inhibition of BACE1 for therapeutic use in Alzheimer's disease.
  Int J Clin Exp Pathol, 3, 618-628.  
19292866 C.E.Hunt, and A.J.Turner (2009).
Cell biology, regulation and inhibition of beta-secretase (BACE-1).
  FEBS J, 276, 1845-1859.  
19326385 J.Y.Lee, and Y.C.Kim (2009).
Combinatorial library synthesis and biological evaluation of pyrazolo[4,3-e][1,4]diazepine as a potential privileged structure.
  ChemMedChem, 4, 733-737.  
19828790 R.Vassar, D.M.Kovacs, R.Yan, and P.C.Wong (2009).
The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential.
  J Neurosci, 29, 12787-12794.  
18180160 A.K.Ghosh, N.Kumaragurubaran, L.Hong, S.Kulkarni, X.Xu, H.B.Miller, D.S.Reddy, V.Weerasena, R.Turner, W.Chang, G.Koelsch, and J.Tang (2008).
Potent memapsin 2 (beta-secretase) inhibitors: design, synthesis, protein-ligand X-ray structure, and in vivo evaluation.
  Bioorg Med Chem Lett, 18, 1031-1036.
PDB code: 2vkm
18625451 A.K.Ghosh, S.Gemma, and J.Tang (2008).
beta-Secretase as a therapeutic target for Alzheimer's disease.
  Neurotherapeutics, 5, 399-408.  
18673212 C.Venugopal, C.M.Demos, K.S.Rao, M.A.Pappolla, and K.Sambamurti (2008).
Beta-secretase: structure, function, and evolution.
  CNS Neurol Disord Drug Targets, 7, 278-294.  
18378702 H.Shimizu, A.Tosaki, K.Kaneko, T.Hisano, T.Sakurai, and N.Nukina (2008).
Crystal structure of an active form of BACE1, an enzyme responsible for amyloid beta protein production.
  Mol Cell Biol, 28, 3663-3671.
PDB codes: 2zhr 2zhs 2zht 2zhu 2zhv
17963207 A.Barazza, M.Götz, S.A.Cadamuro, P.Goettig, M.Willem, H.Steuber, T.Kohler, A.Jestel, P.Reinemer, C.Renner, W.Bode, and L.Moroder (2007).
Macrocyclic statine-based inhibitors of BACE-1.
  Chembiochem, 8, 2078-2091.  
17599084 M.N.Pangalos, L.E.Schechter, and O.Hurko (2007).
Drug development for CNS disorders: strategies for balancing risk and reducing attrition.
  Nat Rev Drug Discov, 6, 521-532.  
17690926 N.J.English (2007).
Calculation of binding affinities of HIV-1 RT and beta-secretase inhibitors using the linear interaction energy method with explicit and continuum solvation approaches.
  J Mol Model, 13, 1081-1097.  
19415126 S.L.Cole, and R.Vassar (2007).
The Basic Biology of BACE1: A Key Therapeutic Target for Alzheimer's Disease.
  Curr Genomics, 8, 509-530.  
16216580 A.A.Gorfe, and A.Caflisch (2005).
Functional plasticity in the substrate binding site of beta-secretase.
  Structure, 13, 1487-1498.  
15485862 G.G.Westmeyer, M.Willem, S.F.Lichtenthaler, G.Lurman, G.Multhaup, I.Assfalg-Machleidt, K.Reiss, P.Saftig, and C.Haass (2004).
Dimerization of beta-site beta-amyloid precursor protein-cleaving enzyme.
  J Biol Chem, 279, 53205-53212.  
15197182 X.P.Huang, W.P.Chang, G.Koelsch, R.T.Turner, F.Lupu, and J.Tang (2004).
Internalization of exogenously added memapsin 2 (beta-secretase) ectodomain by cells is mediated by amyloid precursor protein.
  J Biol Chem, 279, 37886-37894.  
12740808 B.Schmidt (2003).
Aspartic proteases involved in Alzheimer's disease.
  Chembiochem, 4, 366-378.  
  12511580 T.E.Golde (2003).
Alzheimer disease therapy: can the amyloid cascade be halted?
  J Clin Invest, 111, 11-18.  
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 code is shown on the right.

 

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