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PDBsum entry 2q7r
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Membrane protein, lipid transport PDB id
2q7r

 

 

 

 

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Contents
Protein chains
140 a.a. *
148 a.a. *
Ligands
3CS ×6
* Residue conservation analysis
PDB id:
2q7r
Name: Membrane protein, lipid transport
Title: Crystal structure of human flap with an iodinated analog of mk-591
Structure: Arachidonate 5-lipoxygenase-activating protein. Chain: a, b, c, d, e, f. Synonym: flap, mk-886-binding protein. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: alox5ap, flap. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008.
Resolution:
4.00Å     R-factor:   0.268     R-free:   0.281
Authors: A.D.Ferguson
Key ref:
A.D.Ferguson et al. (2007). Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein. Science, 317, 510-512. PubMed id: 17600184 DOI: 10.1126/science.1144346
Date:
07-Jun-07     Release date:   21-Aug-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P20292  (AL5AP_HUMAN) -  Arachidonate 5-lipoxygenase-activating protein from Homo sapiens
Seq:
Struc: 		161 a.a.
140 a.a.
Protein chains
Pfam   ArchSchema ?
P20292  (AL5AP_HUMAN) -  Arachidonate 5-lipoxygenase-activating protein from Homo sapiens
Seq:
Struc: 		161 a.a.
148 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 

 
DOI no: 10.1126/science.1144346 Science 317:510-512 (2007)
PubMed id: 17600184  
 
 
Crystal structure of inhibitor-bound human 5-lipoxygenase-activating protein.
A.D.Ferguson, B.M.McKeever, S.Xu, D.Wisniewski, D.K.Miller, T.T.Yamin, R.H.Spencer, L.Chu, F.Ujjainwalla, B.R.Cunningham, J.F.Evans, J.W.Becker.
 
  ABSTRACT  
 
Leukotrienes are proinflammatory products of arachidonic acid oxidation by 5-lipoxygenase that have been shown to be involved in respiratory and cardiovascular diseases. The integral membrane protein FLAP is essential for leukotriene biosynthesis. We describe the x-ray crystal structures of human FLAP in complex with two leukotriene biosynthesis inhibitors at 4.0 and 4.2 angstrom resolution, respectively. The structures show that inhibitors bind in membrane-embedded pockets of FLAP, which suggests how these inhibitors prevent arachidonic acid from binding to FLAP and subsequently being transferred to 5-lipoxygenase, thereby preventing leukotriene biosynthesis. This structural information provides a platform for the development of therapeutics for respiratory and cardiovascular diseases.
 
  Selected figure(s)  
 
Figure 1.
Fig. 1. (A) Chemical structures of MK-591 and (B) an iodinated analog of MK-591. (C) The FLAP monomer viewed parallel to the nuclear membrane with red helices and green loops. The unstructured C terminus of FLAP (residues 141 to 161) extends beyond G140. (D) The FLAP trimer with monomers colored green, cyan, and magenta. The view is given parallel to the nuclear membrane. Bound inhibitor molecules are shown as stick models with yellow carbon atoms, blue nitrogen atoms, red oxygen atoms, and purple iodine atoms. 		Figure 2.
Fig. 2. Electrostatic surface of FLAP. The view is given (A) parallel to the nuclear membrane, (B) from the cytosol, and (C) from the lumen. One of the three surface grooves has been circled. The cytosolic and lumenal ends of the trimer are positively charged and negatively charged, respectively. (D) Central pocket of FLAP as calculated by CASTp (Computed Atlas of Surface Topography of proteins) (28). Bound inhibitor molecules are shown as stick models with green carbon atoms, blue nitrogen atoms, red oxygen atoms, and purple iodine atoms, and the trimer is shown as a white coil. The front of this pocket has been removed for clarity. The lumenal entrance to this pocket is formed by negatively charged helices. The negatively charged constriction within the membrane is formed by residues Q58 and D62. The surfaces are colored by electrostatic potential with blue and red corresponding to +40 kT and –40 kT.
 
  The above figures are reprinted by permission from the AAAs: Science (2007, 317, 510-512) copyright 2007.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  21428697 A.Oakley (2011).
Glutathione transferases: a structural perspective.
  Drug Metab Rev, 43, 138-151.  
21233389 N.C.Gilbert, S.G.Bartlett, M.T.Waight, D.B.Neau, W.E.Boeglin, A.R.Brash, and M.E.Newcomer (2011).
The structure of human 5-lipoxygenase.
  Science, 331, 217-219.
PDB code: 3o8y
  21495795 R.Morgenstern, J.Zhang, and K.Johansson (2011).
Microsomal glutathione transferase 1: mechanism and functional roles.
  Drug Metab Rev, 43, 300-306.  
20182424 G.Bain, C.D.King, M.Rewolinski, K.Schaab, A.M.Santini, D.Shapiro, M.Moran, S.van de Wetering de Rooij, A.F.Roffel, P.Schuilenga-Hut, G.L.Milne, D.S.Lorrain, Y.Li, J.M.Arruda, J.H.Hutchinson, P.Prasit, and J.F.Evans (2010).
Pharmacodynamics and pharmacokinetics of AM103, a novel inhibitor of 5-lipoxygenase-activating protein (FLAP).
  Clin Pharmacol Ther, 87, 437-444.  
20196071 G.Kefala, C.Ahn, M.Krupa, L.Esquivies, I.Maslennikov, W.Kwiatkowski, and S.Choe (2010).
Structures of the OmpF porin crystallized in the presence of foscholine-12.
  Protein Sci, 19, 1117-1125.
PDB codes: 3k19 3k1b
19826804 K.McLuskey, A.W.Roszak, Y.Zhu, and N.W.Isaacs (2010).
Crystal structures of all-alpha type membrane proteins.
  Eur Biophys J, 39, 723-755.  
20667175 K.R.Vinothkumar, and R.Henderson (2010).
Structures of membrane proteins.
  Q Rev Biophys, 43, 65.  
20739006 M.Miyano, H.Ago, H.Saino, T.Hori, and K.Ida (2010).
Internally bridging water molecule in transmembrane alpha-helical kink.
  Curr Opin Struct Biol, 20, 456-463.  
20605783 S.C.Pawelzik, N.R.Uda, L.Spahiu, C.Jegerschöld, P.Stenberg, H.Hebert, R.Morgenstern, and P.J.Jakobsson (2010).
Identification of key residues determining species differences in inhibitor binding of microsomal prostaglandin E synthase-1.
  J Biol Chem, 285, 29254-29261.  
19171966 A.M.Karmali, T.L.Blundell, and N.Furnham (2009).
Model-building strategies for low-resolution X-ray crystallographic data.
  Acta Crystallogr D Biol Crystallogr, 65, 121-127.  
19561298 A.Maekawa, B.Balestrieri, K.F.Austen, and Y.Kanaoka (2009).
GPR17 is a negative regulator of the cysteinyl leukotriene 1 receptor response to leukotriene D4.
  Proc Natl Acad Sci U S A, 106, 11685-11690.  
19031011 F.A.Hays, Z.Roe-Zurz, M.Li, L.Kelly, F.Gruswitz, A.Sali, and R.M.Stroud (2009).
Ratiocinative screen of eukaryotic integral membrane protein expression and solubilization for structure determination.
  J Struct Funct Genomics, 10, 9.  
20150962 G.Riccioni, A.Zanasi, N.Vitulano, B.Mancini, and N.D'Orazio (2009).
Leukotrienes in atherosclerosis: new target insights and future therapy perspectives.
  Mediators Inflamm, 2009, 737282.  
19416719 J.Alander, J.Lengqvist, P.J.Holm, R.Svensson, P.Gerbaux, R.H.Heuvel, H.Hebert, W.J.Griffiths, R.N.Armstrong, and R.Morgenstern (2009).
Microsomal glutathione transferase 1 exhibits one-third-of-the-sites-reactivity towards glutathione.
  Arch Biochem Biophys, 487, 42-48.  
18777160 L.Xing, R.G.Kurumbail, R.B.Frazier, M.S.Davies, H.Fujiwara, R.A.Weinberg, J.K.Gierse, N.Caspers, J.S.Carter, J.J.McDonald, W.M.Moore, and M.L.Vazquez (2009).
Homo-timeric structural model of human microsomal prostaglandin E synthase-1 and characterization of its substrate/inhibitor binding interactions.
  J Comput Aided Mol Des, 23, 13-24.  
20040113 M.Freigassner, H.Pichler, and A.Glieder (2009).
wTuning microbial hosts for membrane protein production.
  Microb Cell Fact, 8, 69.  
19061901 M.Li, F.A.Hays, Z.Roe-Zurz, L.Vuong, L.Kelly, C.M.Ho, R.M.Robbins, U.Pieper, J.D.O'Connell, L.J.Miercke, K.M.Giacomini, A.Sali, and R.M.Stroud (2009).
Selecting optimum eukaryotic integral membrane proteins for structure determination by rapid expression and solubilization screening.
  J Mol Biol, 385, 820-830.  
19244215 M.W.Buczynski, D.S.Dumlao, and E.A.Dennis (2009).
Thematic Review Series: Proteomics. An integrated omics analysis of eicosanoid biology.
  J Lipid Res, 50, 1015-1038.  
  18987389 O.Rådmark, and B.Samuelsson (2009).
5-Lipoxygenase: mechanisms of regulation.
  J Lipid Res, 50, S40-S45.  
18984580 T.Hammarberg, M.Hamberg, A.Wetterholm, H.Hansson, B.Samuelsson, and J.Z.Haeggström (2009).
Mutation of a Critical Arginine in Microsomal Prostaglandin E Synthase-1 Shifts the Isomerase Activity to a Reductase Activity That Converts Prostaglandin H2 into Prostaglandin F2{alpha}.
  J Biol Chem, 284, 301-305.  
18834304 T.Shimizu (2009).
Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation.
  Annu Rev Pharmacol Toxicol, 49, 123-150.  
19360018 Z.E.Newby, J.D.O'Connell, F.Gruswitz, F.A.Hays, W.E.Harries, I.M.Harwood, J.D.Ho, J.K.Lee, D.F.Savage, L.J.Miercke, and R.M.Stroud (2009).
A general protocol for the crystallization of membrane proteins for X-ray structural investigation.
  Nat Protoc, 4, 619-637.  
19075240 A.K.Mandal, P.B.Jones, A.M.Bair, P.Christmas, D.Miller, T.T.Yamin, D.Wisniewski, J.Menke, J.F.Evans, B.T.Hyman, B.Bacskai, M.Chen, D.M.Lee, B.Nikolic, and R.J.Soberman (2008).
The nuclear membrane organization of leukotriene synthesis.
  Proc Natl Acad Sci U S A, 105, 20434-20439.  
18931305 A.Maekawa, Y.Kanaoka, W.Xing, and K.F.Austen (2008).
Functional recognition of a distinct receptor preferential for leukotriene E4 in mice lacking the cysteinyl leukotriene 1 and 2 receptors.
  Proc Natl Acad Sci U S A, 105, 16695-16700.  
18682561 C.Jegerschöld, S.C.Pawelzik, P.Purhonen, P.Bhakat, K.R.Gheorghe, N.Gyobu, K.Mitsuoka, R.Morgenstern, P.J.Jakobsson, and H.Hebert (2008).
Structural basis for induced formation of the inflammatory mediator prostaglandin E2.
  Proc Natl Acad Sci U S A, 105, 11110-11115.
PDB code: 3dww
18451787 D.Drew, S.Newstead, Y.Sonoda, H.Kim, G.von Heijne, and S.Iwata (2008).
GFP-based optimization scheme for the overexpression and purification of eukaryotic membrane proteins in Saccharomyces cerevisiae.
  Nat Protoc, 3, 784-798.  
18321962 D.J.Müller, N.Wu, and K.Palczewski (2008).
Vertebrate membrane proteins: structure, function, and insights from biophysical approaches.
  Pharmacol Rev, 60, 43-78.  
18674618 E.P.Carpenter, K.Beis, A.D.Cameron, and S.Iwata (2008).
Overcoming the challenges of membrane protein crystallography.
  Curr Opin Struct Biol, 18, 581-586.  
18550820 S.Reckel, S.Sobhanifar, B.Schneider, F.Junge, D.Schwarz, F.Durst, F.Löhr, P.Güntert, F.Bernhard, and V.Dötsch (2008).
Transmembrane segment enhanced labeling as a tool for the backbone assignment of alpha-helical membrane proteins.
  Proc Natl Acad Sci U S A, 105, 8262-8267.  
17709746 S.Newstead, H.Kim, G.von Heijne, S.Iwata, and D.Drew (2007).
High-throughput fluorescent-based optimization of eukaryotic membrane protein overexpression and purification in Saccharomyces cerevisiae.
  Proc Natl Acad Sci U S A, 104, 13936-13941.  
  18084092 S.Xu, B.M.McKeever, D.Wisniewski, D.K.Miller, R.H.Spencer, L.Chu, F.Ujjainwalla, T.T.Yamin, J.F.Evans, J.W.Becker, and A.D.Ferguson (2007).
Expression, purification and crystallization of human 5-lipoxygenase-activating protein with leukotriene-biosynthesis inhibitors.
  Acta Crystallogr Sect F Struct Biol Cryst Commun, 63, 1054-1057.  
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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