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PDBsum entry 1dcy

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Hydrolase/hydrolase inhibitor PDB id
1dcy
Jmol PyMol
Contents
Protein chain
124 a.a. *
Ligands
I3N
Metals
_CA ×2
Waters ×13
* Residue conservation analysis
PDB id:
1dcy
Name: Hydrolase/hydrolase inhibitor
Title: Crystal structure of human s-pla2 in complex with indole 3 active site inhibitor
Structure: Phospholipase a2. Chain: a. Synonym: hnp-spla2. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606
Biol. unit: Dimer (from PQS)
Resolution:
2.70Å     R-factor:   0.218     R-free:   0.269
Authors: N.Y.Chirgadze,R.W.Schevitz,J.-P.Wery
Key ref: R.W.Schevitz et al. (1995). Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2. Nat Struct Biol, 2, 458-465. PubMed id: 7664108
Date:
05-Nov-99     Release date:   12-Nov-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P14555  (PA2GA_HUMAN) -  Phospholipase A2, membrane associated
Seq:
Struc:
144 a.a.
124 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.1.1.4  - Phospholipase A(2).
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Phosphatidylcholine + H2O = 1-acylglycerophosphocholine + a carboxylate
Phosphatidylcholine
+ H(2)O
= 1-acylglycerophosphocholine
+
carboxylate
Bound ligand (Het Group name = I3N)
matches with 48.00% similarity
      Cofactor: Ca(2+)
Molecule diagrams generated from .mol files obtained from the KEGG ftp site
 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     extracellular region   9 terms 
  Biological process     phosphatidylglycerol acyl-chain remodeling   17 terms 
  Biochemical function     hydrolase activity     6 terms  

 

 
    reference    
 
 
Nat Struct Biol 2:458-465 (1995)
PubMed id: 7664108  
 
 
Structure-based design of the first potent and selective inhibitor of human non-pancreatic secretory phospholipase A2.
R.W.Schevitz, N.J.Bach, D.G.Carlson, N.Y.Chirgadze, D.K.Clawson, R.D.Dillard, S.E.Draheim, L.W.Hartley, N.D.Jones, E.D.Mihelich.
 
  ABSTRACT  
 
A lead compound obtained from a high volume human non-pancreatic secretory phospholipase A2 (hnps-PLA2) screen has been developed into a potent inhibitor using detailed structural knowledge of inhibitor binding to the enzyme active site. Four crystal structures of hnps-PLA2 complexed with a series of increasingly potent indole inhibitors were determined and used as the structural basis for both understanding this binding and providing valuable insights for further development. The application of structure-based drug design has made possible improvements in the binding of this screening lead to the enzyme by nearly three orders of magnitude. Furthermore, the optimized structure (LY311727) displayed 1,500-fold selectivity when assayed against porcine pancreatic s-PLA2.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
19603203 C.E.Cassidy, and W.N.Setzer (2010).
Cancer-relevant biochemical targets of cytotoxic Lonchocarpus flavonoids: a molecular docking analysis.
  J Mol Model, 16, 311-326.  
20130961 V.D.Mouchlis, T.M.Mavromoustakos, and G.Kokotos (2010).
Design of new secreted phospholipase A2 inhibitors based on docking calculations by modifying the pharmacophore segments of the FPL67047XX inhibitor.
  J Comput Aided Mol Des, 24, 107-115.  
19576246 A.Huwiler, and J.Pfeilschifter (2009).
Lipids as targets for novel anti-inflammatory therapies.
  Pharmacol Ther, 124, 96.  
  19011112 J.E.Burke, and E.A.Dennis (2009).
Phospholipase A2 structure/function, mechanism, and signaling.
  J Lipid Res, 50, S237-S242.  
19222850 J.O.Leite, U.Vaishnav, M.Puglisi, H.Fraser, J.Trias, and M.L.Fernandez (2009).
A-002 (Varespladib), a phospholipase A2 inhibitor, reduces atherosclerosis in guinea pigs.
  BMC Cardiovasc Disord, 9, 7.  
19065693 M.C.Monti, A.Casapullo, C.N.Cavasotto, A.Tosco, F.Dal Piaz, A.Ziemys, L.Margarucci, and R.Riccio (2009).
The binding mode of petrosaspongiolide M to the human group IIA phospholipase A(2): exploring the role of covalent and noncovalent interactions in the inhibition process.
  Chemistry, 15, 1155-1163.  
19765281 M.M.Thwin, E.Douni, P.Arjunan, G.Kollias, P.V.Kumar, and P.Gopalakrishnakone (2009).
Suppressive effect of secretory phospholipase A2 inhibitory peptide on interleukin-1beta-induced matrix metalloproteinase production in rheumatoid synovial fibroblasts, and its antiarthritic activity in hTNFtg mice.
  Arthritis Res Ther, 11, R138.  
18564366 A.L.Taylor, J.V.Bonventre, T.F.Uliasz, J.A.Hewett, and S.J.Hewett (2008).
Cytosolic phospholipase A2 alpha inhibition prevents neuronal NMDA receptor-stimulated arachidonic acid mobilization and prostaglandin production but not subsequent cell death.
  J Neurochem, 106, 1828-1840.  
18405237 G.Lambeau, and M.H.Gelb (2008).
Biochemistry and physiology of mammalian secreted phospholipases A2.
  Annu Rev Biochem, 77, 495-520.  
18336573 M.A.Balboa, R.Pérez, and J.Balsinde (2008).
Calcium-independent phospholipase A2 mediates proliferation of human promonocytic U937 cells.
  FEBS J, 275, 1915-1924.  
18605714 R.C.Oslund, N.Cermak, and M.H.Gelb (2008).
Highly specific and broadly potent inhibitors of mammalian secreted phospholipases A2.
  J Med Chem, 51, 4708-4714.  
17505111 G.Gopalan, M.M.Thwin, P.Gopalakrishnakone, and K.Swaminathan (2007).
Structural and pharmacological comparison of daboiatoxin from Daboia russelli siamensis with viperotoxin F and vipoxin from other vipers.
  Acta Crystallogr D Biol Crystallogr, 63, 722-729.
PDB code: 2h4c
17701137 J.Lättig, M.Böhl, P.Fischer, S.Tischer, C.Tietböhl, M.Menschikowski, H.O.Gutzeit, P.Metz, and M.T.Pisabarro (2007).
Mechanism of inhibition of human secretory phospholipase A2 by flavonoids: rationale for lead design.
  J Comput Aided Mol Des, 21, 473-483.  
16686528 B.P.Smart, R.C.Oslund, L.A.Walsh, and M.H.Gelb (2006).
The first potent inhibitor of mammalian group X secreted phospholipase A2: elucidation of sites for enhanced binding.
  J Med Chem, 49, 2858-2860.  
16596639 N.Singh, T.Jabeen, A.Pal, S.Sharma, M.Perbandt, C.Betzel, and T.P.Singh (2006).
Crystal structures of the complexes of a group IIA phospholipase A2 with two natural anti-inflammatory agents, anisic acid, and atropine reveal a similar mode of binding.
  Proteins, 64, 89.
PDB codes: 1sv3 2arm
16689598 R.Bitetti-Putzer, A.R.Dinner, W.Yang, and M.Karplus (2006).
Conformational sampling via a self-regulating effective energy surface.
  J Chem Phys, 124, 174901.  
15659372 G.Singh, J.Jasti, K.Saravanan, S.Sharma, P.Kaur, A.Srinivasan, and T.P.Singh (2005).
Crystal structure of the complex formed between a group I phospholipase A2 and a naturally occurring fatty acid at 2.7 A resolution.
  Protein Sci, 14, 395-400.
PDB code: 1tc8
16301791 T.Jabeen, N.Singh, R.K.Singh, S.Sharma, R.K.Somvanshi, S.Dey, and T.P.Singh (2005).
Non-steroidal anti-inflammatory drugs as potent inhibitors of phospholipase A2: structure of the complex of phospholipase A2 with niflumic acid at 2.5 Angstroms resolution.
  Acta Crystallogr D Biol Crystallogr, 61, 1579-1586.
PDB code: 1td7
12616631 K.A.Hansford, R.C.Reid, C.I.Clark, J.D.Tyndall, M.W.Whitehouse, T.Guthrie, R.P.McGeary, K.Schafer, J.L.Martin, and D.P.Fairlie (2003).
D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A2 (IIa) with antiinflammatory activity.
  Chembiochem, 4, 181-185.
PDB codes: 1j1a 1kqu
12783578 K.F.Scott, G.G.Graham, and K.J.Bryant (2003).
Secreted phospholipase A2 enzymes as therapeutic targets.
  Expert Opin Ther Targets, 7, 427-440.  
12782627 S.Beck, G.Lambeau, K.Scholz-Pedretti, M.H.Gelb, M.J.Janssen, S.H.Edwards, D.C.Wilton, J.Pfeilschifter, and M.Kaszkin (2003).
Potentiation of tumor necrosis factor alpha-induced secreted phospholipase A2 (sPLA2)-IIA expression in mesangial cells by an autocrine loop involving sPLA2 and peroxisome proliferator-activated receptor alpha activation.
  J Biol Chem, 278, 29799-29812.  
12676927 W.K.Han, A.Sapirstein, C.C.Hung, A.Alessandrini, and J.V.Bonventre (2003).
Cross-talk between cytosolic phospholipase A2 alpha (cPLA2 alpha) and secretory phospholipase A2 (sPLA2) in hydrogen peroxide-induced arachidonic acid release in murine mesangial cells: sPLA2 regulates cPLA2 alpha activity that is responsible for arachidonic acid release.
  J Biol Chem, 278, 24153-24163.  
12359733 A.G.Singer, F.Ghomashchi, C.Le Calvez, J.Bollinger, S.Bezzine, M.Rouault, M.Sadilek, E.Nguyen, M.Lazdunski, G.Lambeau, and M.H.Gelb (2002).
Interfacial kinetic and binding properties of the complete set of human and mouse groups I, II, V, X, and XII secreted phospholipases A2.
  J Biol Chem, 277, 48535-48549.  
11934806 G.C.h.Beck, B.A.Yard, J.Schulte, R.Oberacker, K.van Ackern, F.J.van Der Woude, M.Krimsky, M.Kaszkin, and S.Yedgar (2002).
Inhibition of LPS-induced chemokine production in human lung endothelial cells by lipid conjugates anchored to the membrane.
  Br J Pharmacol, 135, 1665-1674.  
11741884 N.Degousee, F.Ghomashchi, E.Stefanski, A.Singer, B.P.Smart, N.Borregaard, R.Reithmeier, T.F.Lindsay, C.Lichtenberger, W.Reinisch, G.Lambeau, J.Arm, J.Tischfield, M.H.Gelb, and B.B.Rubin (2002).
Groups IV, V, and X phospholipases A2s in human neutrophils: role in eicosanoid production and gram-negative bacterial phospholipid hydrolysis.
  J Biol Chem, 277, 5061-5073.  
12186870 V.Chandra, J.Jasti, P.Kaur, S.Dey, M.Perbandt, A.Srinivasan, C.h.Betzel, and T.P.Singh (2002).
Crystal structure of a complex formed between a snake venom phospholipase A(2) and a potent peptide inhibitor Phe-Leu-Ser-Tyr-Lys at 1.8 A resolution.
  J Biol Chem, 277, 41079-41085.
PDB code: 1jq9
12161451 Y.H.Pan, B.Z.Yu, A.G.Singer, F.Ghomashchi, G.Lambeau, M.H.Gelb, M.K.Jain, and B.J.Bahnson (2002).
Crystal structure of human group X secreted phospholipase A2. Electrostatically neutral interfacial surface targets zwitterionic membranes.
  J Biol Chem, 277, 29086-29093.
PDB codes: 1le6 1le7
11168795 A.Schadow, K.Scholz-Pedretti, G.Lambeau, M.H.Gelb, G.Fürstenberger, J.Pfeilschifter, and M.Kaszkin (2001).
Characterization of group X phospholipase A(2) as the major enzyme secreted by human keratinocytes and its regulation by the phorbol ester TPA.
  J Invest Dermatol, 116, 31-39.  
11571275 N.Degousee, E.Stefanski, T.F.Lindsay, D.A.Ford, R.Shahani, C.A.Andrews, D.J.Thuerauf, C.C.Glembotski, T.J.Nevalainen, J.Tischfield, and B.B.Rubin (2001).
p38 MAPK regulates group IIa phospholipase A2 expression in interleukin-1beta -stimulated rat neonatal cardiomyocytes.
  J Biol Chem, 276, 43842-43849.  
11159446 S.A.Tatulian (2001).
Toward understanding interfacial activation of secretory phospholipase A2 (PLA2): membrane surface properties and membrane-induced structural changes in the enzyme contribute synergistically to PLA2 activation.
  Biophys J, 80, 789-800.  
11141053 W.H.Lee, M.T.da Silva Giotto, S.Marangoni, M.H.Toyama, I.Polikarpov, and R.C.Garratt (2001).
Structural basis for low catalytic activity in Lys49 phospholipases A2--a hypothesis: the crystal structure of piratoxin II complexed to fatty acid.
  Biochemistry, 40, 28-36.
PDB code: 1qll
10671511 J.Balsinde, M.A.Balboa, S.Yedgar, and E.A.Dennis (2000).
Group V phospholipase A(2)-mediated oleic acid mobilization in lipopolysaccharide-stimulated P388D(1) macrophages.
  J Biol Chem, 275, 4783-4786.  
10848980 M.Alaoui El Azher, N.Havet, M.Singer, C.Dumarey, and L.Touqui (2000).
Inhibition by unsaturated fatty acids of type II secretory phospholipase A2 synthesis in guinea-pig alveolar macrophages evidence for the eicosanoid-independent pathway.
  Eur J Biochem, 267, 3633-3639.  
10625636 P.G.Hains, K.L.Sung, A.Tseng, and K.W.Broady (2000).
Functional characteristics of a phospholipase A(2) inhibitor from Notechis ater serum.
  J Biol Chem, 275, 983-991.  
10652303 S.Bezzine, R.S.Koduri, E.Valentin, M.Murakami, I.Kudo, F.Ghomashchi, M.Sadilek, G.Lambeau, and M.H.Gelb (2000).
Exogenously added human group X secreted phospholipase A(2) but not the group IB, IIA, and V enzymes efficiently release arachidonic acid from adherent mammalian cells.
  J Biol Chem, 275, 3179-3191.  
10473537 J.Balsinde, H.Shinohara, L.J.Lefkowitz, C.A.Johnson, M.A.Balboa, and E.A.Dennis (1999).
Group V phospholipase A(2)-dependent induction of cyclooxygenase-2 in macrophages.
  J Biol Chem, 274, 25967-25970.  
10331081 J.Balsinde, M.A.Balboa, P.A.Insel, and E.A.Dennis (1999).
Regulation and inhibition of phospholipase A2.
  Annu Rev Pharmacol Toxicol, 39, 175-189.  
9915849 M.Murakami, T.Kambe, S.Shimbara, and I.Kudo (1999).
Functional coupling between various phospholipase A2s and cyclooxygenases in immediate and delayed prostanoid biosynthetic pathways.
  J Biol Chem, 274, 3103-3115.  
10531345 M.Murakami, T.Kambe, S.Shimbara, K.Higashino, K.Hanasaki, H.Arita, M.Horiguchi, M.Arita, H.Arai, K.Inoue, and I.Kudo (1999).
Different functional aspects of the group II subfamily (Types IIA and V) and type X secretory phospholipase A(2)s in regulating arachidonic acid release and prostaglandin generation. Implications of cyclooxygenase-2 induction and phospholipid scramblase-mediated cellular membrane perturbation.
  J Biol Chem, 274, 31435-31444.  
10438497 P.Y.Wang, and R.S.Munford (1999).
CD14-dependent internalization and metabolism of extracellular phosphatidylinositol by monocytes.
  J Biol Chem, 274, 23235-23241.  
9593733 G.Atsumi, M.Tajima, A.Hadano, Y.Nakatani, M.Murakami, and I.Kudo (1998).
Fas-induced arachidonic acid release is mediated by Ca2+-independent phospholipase A2 but not cytosolic phospholipase A2, which undergoes proteolytic inactivation.
  J Biol Chem, 273, 13870-13877.  
9739049 L.Arbibe, K.Koumanov, D.Vial, C.Rougeot, G.Faure, N.Havet, S.Longacre, B.B.Vargaftig, G.Béréziat, D.R.Voelker, C.Wolf, and L.Touqui (1998).
Generation of lyso-phospholipids from surfactant in acute lung injury is mediated by type-II phospholipase A2 and inhibited by a direct surfactant protein A-phospholipase A2 protein interaction.
  J Clin Invest, 102, 1152-1160.  
9603953 M.Murakami, S.Shimbara, T.Kambe, H.Kuwata, M.V.Winstead, J.A.Tischfield, and I.Kudo (1998).
The functions of five distinct mammalian phospholipase A2S in regulating arachidonic acid release. Type IIa and type V secretory phospholipase A2S are functionally redundant and act in concert with cytosolic phospholipase A2.
  J Biol Chem, 273, 14411-14423.  
9691100 Y.Weinrauch, C.Abad, N.S.Liang, S.F.Lowry, and J.Weiss (1998).
Mobilization of potent plasma bactericidal activity during systemic bacterial challenge. Role of group IIA phospholipase A2.
  J Clin Invest, 102, 633-638.  
9247353 E.Hurt-Camejo, and G.Camejo (1997).
Potential involvement of type II phospholipase A2 in atherosclerosis.
  Atherosclerosis, 132, 1-8.  
8727316 F.Zhou, and K.Schulten (1996).
Molecular dynamics study of phospholipase A2 on a membrane surface.
  Proteins, 25, 12-27.  
8768903 H.J.Böhm (1996).
Current computational tools for de novo ligand design.
  Curr Opin Biotechnol, 7, 433-436.  
8636097 J.Balsinde, and E.A.Dennis (1996).
Distinct roles in signal transduction for each of the phospholipase A2 enzymes present in P388D1 macrophages.
  J Biol Chem, 271, 6758-6765.  
8785272 N.D.Silva, and F.G.Prendergast (1996).
Tryptophan dynamics of the FK506 binding protein: time-resolved fluorescence and simulations.
  Biophys J, 70, 1122-1137.  
8910365 R.M.Kramer, E.F.Roberts, S.L.Um, A.G.Börsch-Haubold, S.P.Watson, M.J.Fisher, and J.A.Jakubowski (1996).
p38 mitogen-activated protein kinase phosphorylates cytosolic phospholipase A2 (cPLA2) in thrombin-stimulated platelets. Evidence that proline-directed phosphorylation is not required for mobilization of arachidonic acid by cPLA2.
  J Biol Chem, 271, 27723-27729.  
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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