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PDBsum entry 2e56
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Lipid binding protein PDB id
2e56

 

 

 

 

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Contents
Protein chain
144 a.a. *
Ligands
NAG ×2
MYR ×3
Waters ×143
* Residue conservation analysis
PDB id:
2e56
Name: Lipid binding protein
Title: Crystal structure of human md-2
Structure: Lymphocyte antigen 96. Chain: a. Synonym: md-2 protein, esop-1. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ly96, esop1, md2. Expressed in: pichia pastoris. Expression_system_taxid: 4922.
Resolution:
2.00Å     R-factor:   0.196     R-free:   0.249
Authors: U.Ohto,Y.Satow
Key ref:
U.Ohto et al. (2007). Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa. Science, 316, 1632-1634. PubMed id: 17569869 DOI: 10.1126/science.1139111
Date:
19-Dec-06     Release date:   26-Jun-07    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
Q9Y6Y9  (LY96_HUMAN) -  Lymphocyte antigen 96 from Homo sapiens
Seq:
Struc: 		160 a.a.
144 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.1139111 Science 316:1632-1634 (2007)
PubMed id: 17569869  
 
 
Crystal structures of human MD-2 and its complex with antiendotoxic lipid IVa.
U.Ohto, K.Fukase, K.Miyake, Y.Satow.
 
  ABSTRACT  
 
Endotoxic lipopolysaccharide (LPS) with potent immunostimulatory activity is recognized by the receptor complex of MD-2 and Toll-like receptor 4. Crystal structures of human MD-2 and its complex with the antiendotoxic tetra-acylated lipid A core of LPS have been determined at 2.0 and 2.2 angstrom resolutions, respectively. MD-2 shows a deep hydrophobic cavity sandwiched by two beta sheets, in which four acyl chains of the ligand are fully confined. The phosphorylated glucosamine moieties are located at the entrance to the cavity. These structures suggest that MD-2 plays a principal role in endotoxin recognition and provide a basis for antiseptic drug development.
 
  Selected figure(s)  
 
Figure 2.
Fig. 2. Stereo ribbon model of human MD-2 in complex with lipid IVa. The N terminus is drawn in blue and the C terminus in red. The ß strands are indicated with their labels, and some amino acid residue numbers are shown. Bound lipid IVa and NAGs as well as cysteine residues are drawn as ball-and-stick models. The two ß sheets are inclined toward each other by about 45°. 		Figure 4.
Fig. 4. Binding pocket and surface properties of MD-2. MD-2 is viewed from a 90° rotation with respect to Fig. 2, and residues of interest are indicated. (A) Protein surface showing hydrophobic and hydrophilic properties. The lipid IVa structure is removed from the complexed structure. Green and red represent hydrophobicity and hydrophilicity, respectively, and the extent is indicated by color darkness. (B) Electrostatic potential surface. Positive and negative potentials are shown in blue and red, respectively. Bound lipid IVa is drawn as a ball-and-stick representation: O in red, N in blue, C in yellow, and P in green.
 
  The above figures are reprinted by permission from the AAAs: Science (2007, 316, 1632-1634) copyright 2007.  
  Figures were selected by the author.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21402551 E.Roh, H.S.Lee, J.A.Kwak, J.T.Hong, S.Y.Nam, S.H.Jung, J.Y.Lee, N.D.Kim, S.B.Han, and Y.Kim (2011).
MD-2 as the target of nonlipid chalcone in the inhibition of endotoxin LPS-induced TLR4 activity.
  J Infect Dis, 203, 1012-1020.  
21481769 I.Botos, D.M.Segal, and D.R.Davies (2011).
The Structural Biology of Toll-like Receptors.
  Structure, 19, 447-459.  
21857663 S.I.Yoon, M.Hong, and I.A.Wilson (2011).
An unusual dimeric structure and assembly for TLR4 regulator RP105-MD-1.
  Nat Struct Mol Biol, 18, 1028-1035.
PDB code: 3rg1
21077829 A.I.Tukhvatulin, D.Y.Logunov, D.N.Shcherbinin, M.M.Shmarov, B.S.Naroditsky, A.V.Gudkov, and A.L.Gintsburg (2010).
Toll-like receptors and their adapter molecules.
  Biochemistry (Mosc), 75, 1098-1114.  
20720015 A.X.Tran, C.Dong, and C.Whitfield (2010).
Structure and functional analysis of LptC, a conserved membrane protein involved in the lipopolysaccharide export pathway in Escherichia coli.
  J Biol Chem, 285, 33529-33539.
PDB code: 3my2
19946286 C.E.Bryant, D.R.Spring, M.Gangloff, and N.J.Gay (2010).
The molecular basis of the host response to lipopolysaccharide.
  Nat Rev Microbiol, 8, 8.  
20381850 C.L.Karp (2010).
Guilt by intimate association: what makes an allergen an allergen?
  J Allergy Clin Immunol, 125, 955.  
  20671419 J.C.Blanco, M.S.Boukhvalova, K.A.Shirey, G.A.Prince, and S.N.Vogel (2010).
New insights for development of a safe and protective RSV vaccine.
  Hum Vaccin, 6, 482-492.  
20388233 J.Horácková, N.Rudenko, M.Golovchenko, and L.Grubhoffer (2010).
Der-p2 ( Dermatophagoides pteronyssinus) allergen-like protein from the hard tick Ixodes ricinus - a novel member of ML (MD-2-related lipid-recognition) domain protein family.
  Parasitology, 137, 1139-1149.  
19949486 M.Xiang, and J.Fan (2010).
Pattern recognition receptor-dependent mechanisms of acute lung injury.
  Mol Med, 16, 69-82.  
20176798 N.Marr, A.M.Hajjar, N.R.Shah, A.Novikov, C.S.Yam, M.Caroff, and R.C.Fernandez (2010).
Substitution of the Bordetella pertussis lipid A phosphate groups with glucosamine is required for robust NF-kappaB activation and release of proinflammatory cytokines in cells expressing human but not murine Toll-like receptor 4-MD-2-CD14.
  Infect Immun, 78, 2060-2069.  
20680392 R.Ostuni, I.Zanoni, and F.Granucci (2010).
Deciphering the complexity of Toll-like receptor signaling.
  Cell Mol Life Sci, 67, 4109-4134.  
20534476 S.I.Yoon, M.Hong, G.W.Han, and I.A.Wilson (2010).
Crystal structure of soluble MD-1 and its interaction with lipid IVa.
  Proc Natl Acad Sci U S A, 107, 10990-10995.
PDB codes: 3mtx 3mu3
20431259 S.Kusumoto, K.Fukase, and T.Shiba (2010).
Key structures of bacterial peptidoglycan and lipopolysaccharide triggering the innate immune system of higher animals: chemical synthesis and functional studies.
  Proc Jpn Acad Ser B Phys Biol Sci, 86, 322-337.  
20617171 S.M.Leal, S.Cowden, Y.C.Hsia, M.A.Ghannoum, M.Momany, and E.Pearlman (2010).
Distinct roles for Dectin-1 and TLR4 in the pathogenesis of Aspergillus fumigatus keratitis.
  PLoS Pathog, 6, e1000976.  
20571035 T.H.Yeats, K.J.Howe, A.J.Matas, G.J.Buda, T.W.Thannhauser, and J.K.Rose (2010).
Mining the surface proteome of tomato (Solanum lycopersicum) fruit for proteins associated with cuticle biogenesis.
  J Exp Bot, 61, 3759-3771.  
18844294 A.Bhunia, H.Mohanram, and S.Bhattacharjya (2009).
Lipopolysaccharide bound structures of the active fragments of fowlicidin-1, a cathelicidin family of antimicrobial and antiendotoxic peptide from chicken, determined by transferred nuclear overhauser effect spectroscopy.
  Biopolymers, 92, 9.  
19060881 A.Trompette, S.Divanovic, A.Visintin, C.Blanchard, R.S.Hegde, R.Madan, P.S.Thorne, M.Wills-Karp, T.L.Gioannini, J.P.Weiss, and C.L.Karp (2009).
Allergenicity resulting from functional mimicry of a Toll-like receptor complex protein.
  Nature, 457, 585-588.  
19252480 B.S.Park, D.H.Song, H.M.Kim, B.S.Choi, H.Lee, and J.O.Lee (2009).
The structural basis of lipopolysaccharide recognition by the TLR4-MD-2 complex.
  Nature, 458, 1191-1195.
PDB code: 3fxi
19531474 C.M.John, M.Liu, and G.A.Jarvis (2009).
Natural phosphoryl and acyl variants of lipid A from Neisseria meningitidis strain 89I differentially induce tumor necrosis factor-alpha in human monocytes.
  J Biol Chem, 284, 21515-21525.  
  18974037 C.R.Raetz, Z.Guan, B.O.Ingram, D.A.Six, F.Song, X.Wang, and J.Zhao (2009).
Discovery of new biosynthetic pathways: the lipid A story.
  J Lipid Res, 50, S103-S108.  
19477055 D.S.Stephens (2009).
Biology and pathogenesis of the evolutionarily successful, obligate human bacterium Neisseria meningitidis.
  Vaccine, 27, B71-B77.  
19595807 I.Botos, L.Liu, Y.Wang, D.M.Segal, and D.R.Davies (2009).
The toll-like receptor 3:dsRNA signaling complex.
  Biochim Biophys Acta, 1789, 667-674.  
19783674 J.Vasl, A.Oblak, T.L.Gioannini, J.P.Weiss, and R.Jerala (2009).
Novel roles of lysines 122, 125, and 58 in functional differences between human and murine MD-2.
  J Immunol, 183, 5138-5145.  
19931471 J.Y.Kang, X.Nan, M.S.Jin, S.J.Youn, Y.H.Ryu, S.Mah, S.H.Han, H.Lee, S.G.Paik, and J.O.Lee (2009).
Recognition of lipopeptide patterns by Toll-like receptor 2-Toll-like receptor 6 heterodimer.
  Immunity, 31, 873-884.
PDB codes: 3a79 3a7b 3a7c
19816595 K.Jung, J.E.Lee, H.Z.Kim, H.M.Kim, B.S.Park, S.I.Hwang, J.O.Lee, S.C.Kim, and G.Y.Koh (2009).
Toll-like receptor 4 decoy, TOY, attenuates gram-negative bacterial sepsis.
  PLoS One, 4, e7403.  
19474110 L.A.O'Neill, C.E.Bryant, and S.L.Doyle (2009).
Therapeutic targeting of Toll-like receptors for infectious and inflammatory diseases and cancer.
  Pharmacol Rev, 61, 177-197.  
18984595 M.J.Karbarz, D.A.Six, and C.R.Raetz (2009).
Purification and characterization of the lipid A 1-phosphatase LpxE of Rhizobium leguminosarum.
  J Biol Chem, 284, 414-425.  
19473973 M.Mancek-Keber, H.Gradisar, M.Iñigo Pestaña, G.Martinez de Tejada, and R.Jerala (2009).
Free thiol group of MD-2 as the target for inhibition of the lipopolysaccharide-induced cell activation.
  J Biol Chem, 284, 19493-19500.  
19928913 M.Piazza, L.Yu, A.Teghanemt, T.Gioannini, J.Weiss, and F.Peri (2009).
Evidence of a specific interaction between new synthetic antisepsis agents and CD14.
  Biochemistry, 48, 12337-12344.  
19321453 N.Resman, J.Vasl, A.Oblak, P.Pristovsek, T.L.Gioannini, J.P.Weiss, and R.Jerala (2009).
Essential roles of hydrophobic residues in both MD-2 and toll-like receptor 4 in activation by endotoxin.
  J Biol Chem, 284, 15052-15060.  
19433546 P.Gross, K.Brandl, C.Dierkes, J.Schölmerich, B.Salzberger, T.Glück, and W.Falk (2009).
Lipopolysaccharide-trap-Fc, a multifunctional agent to battle gram-negative bacteria.
  Infect Immun, 77, 2925-2931.  
19395959 P.Tissières, and J.Pugin (2009).
The role of MD-2 in the opsonophagocytosis of Gram-negative bacteria.
  Curr Opin Infect Dis, 22, 286-291.  
19632992 P.Tissières, T.Araud, A.Ochoda, G.Drifte, I.Dunn-Siegrist, and J.Pugin (2009).
Cooperation between PU.1 and CAAT/enhancer-binding protein beta is necessary to induce the expression of the MD-2 gene.
  J Biol Chem, 284, 26261-26272.  
19493685 R.I.Tapping (2009).
Innate immune sensing and activation of cell surface Toll-like receptors.
  Semin Immunol, 21, 175-184.  
19678854 S.Ichikawa, T.Takai, T.Yashiki, S.Takahashi, K.Okumura, H.Ogawa, D.Kohda, and H.Hatanaka (2009).
Lipopolysaccharide binding of the mite allergen Der f 2.
  Genes Cells, 14, 1055-1065.  
19246554 T.Kawai, and S.Akira (2009).
The roles of TLRs, RLRs and NLRs in pathogen recognition.
  Int Immunol, 21, 317-337.  
19181857 T.Roger, C.Froidevaux, D.Le Roy, M.K.Reymond, A.L.Chanson, D.Mauri, K.Burns, B.M.Riederer, S.Akira, and T.Calandra (2009).
Protection from lethal gram-negative bacterial sepsis by targeting Toll-like receptor 4.
  Proc Natl Acad Sci U S A, 106, 2348-2352.  
20477001 W.R.Thomas (2009).
Molecular mimicry as the key to the dominance of the house dust mite allergen Der p 2.
  Expert Rev Clin Immunol, 5, 233-237.  
19166327 X.Wang, A.A.Ribeiro, Z.Guan, and C.R.Raetz (2009).
Identification of undecaprenyl phosphate-beta-D-galactosamine in Francisella novicida and its function in lipid A modification.
  Biochemistry, 48, 1162-1172.  
18662115 A.K.Randhawa, and T.R.Hawn (2008).
Toll-like receptors: their roles in bacterial recognition and respiratory infections.
  Expert Rev Anti Infect Ther, 6, 479-495.  
18519568 A.Teghanemt, R.L.Widstrom, T.L.Gioannini, and J.P.Weiss (2008).
Isolation of monomeric and dimeric secreted MD-2. Endotoxin.sCD14 and Toll-like receptor 4 ectodomain selectively react with the monomeric form of secreted MD-2.
  J Biol Chem, 283, 21881-21889.  
18668203 C.R.Casella, and T.C.Mitchell (2008).
Putting endotoxin to work for us: monophosphoryl lipid A as a safe and effective vaccine adjuvant.
  Cell Mol Life Sci, 65, 3231-3240.  
18802444 D.Rittirsch, M.A.Flierl, and P.A.Ward (2008).
Harmful molecular mechanisms in sepsis.
  Nat Rev Immunol, 8, 776-787.  
  18541212 K.J.Ishii, S.Koyama, A.Nakagawa, C.Coban, and S.Akira (2008).
Host innate immune receptors and beyond: making sense of microbial infections.
  Cell Host Microbe, 3, 352-363.  
18446139 L.A.O'Neill (2008).
Primer: Toll-like receptor signaling pathways--what do rheumatologists need to know?
  Nat Clin Pract Rheumatol, 4, 319-327.  
18585456 M.S.Jin, and J.O.Lee (2008).
Structures of TLR-ligand complexes.
  Curr Opin Immunol, 20, 414-419.  
18701082 M.S.Jin, and J.O.Lee (2008).
Structures of the toll-like receptor family and its ligand complexes.
  Immunity, 29, 182-191.  
18056837 P.Tissières, I.Dunn-Siegrist, M.Schäppi, G.Elson, R.Comte, V.Nobre, and J.Pugin (2008).
Soluble MD-2 is an acute-phase protein and an opsonin for Gram-negative bacteria.
  Blood, 111, 2122-2131.  
18086818 R.S.Munford (2008).
Sensing gram-negative bacterial lipopolysaccharides: a human disease determinant?
  Infect Immun, 76, 454-465.  
18625310 S.Akashi-Takamura, and K.Miyake (2008).
TLR accessory molecules.
  Curr Opin Immunol, 20, 420-425.  
18650420 S.M.Zimmer, J.Liu, J.L.Clayton, D.S.Stephens, and J.P.Snyder (2008).
Paclitaxel binding to human and murine MD-2.
  J Biol Chem, 283, 27916-27926.  
18780723 T.Kiyokawa, S.Akashi-Takamura, T.Shibata, F.Matsumoto, C.Nishitani, Y.Kuroki, Y.Seto, and K.Miyake (2008).
A single base mutation in the PRAT4A gene reveals differential interaction of PRAT4A with Toll-like receptors.
  Int Immunol, 20, 1407-1415.  
18317019 T.Sigsgaard, H.J.Hoffmann, and P.S.Thorne (2008).
The role of innate immunity in occupational allergy: recent findings.
  Curr Opin Allergy Clin Immunol, 8, 120-125.  
18389479 T.Tanaka, A.Legat, E.Adam, J.Steuve, J.S.Gatot, M.Vandenbranden, L.Ulianov, C.Lonez, J.M.Ruysschaert, E.Muraille, M.Tuynder, M.Goldman, and A.Jacquet (2008).
DiC14-amidine cationic liposomes stimulate myeloid dendritic cells through Toll-like receptor 4.
  Eur J Immunol, 38, 1351-1357.  
18421154 U.Ohto, and Y.Satow (2008).
Crystal twinning of human MD-2 recognizing endotoxin cores of lipopolysaccharide.
  J Synchrotron Radiat, 15, 262-265.  
18203953 V.Jain, A.Halle, K.A.Halmen, E.Lien, M.Charrel-Dennis, S.Ram, D.T.Golenbock, and A.Visintin (2008).
Phagocytosis and intracellular killing of MD-2 opsonized gram-negative bacteria depend on TLR4 signaling.
  Blood, 111, 4637-4645.  
18161744 X.Zhang, and D.Mosser (2008).
Macrophage activation by endogenous danger signals.
  J Pathol, 214, 161-178.  
17979843 B.Beutler (2007).
Neo-ligands for innate immune receptors and the etiology of sterile inflammatory disease.
  Immunol Rev, 220, 113-128.  
17803912 H.M.Kim, B.S.Park, J.I.Kim, S.E.Kim, J.Lee, S.C.Oh, P.Enkhbayar, N.Matsushima, H.Lee, O.J.Yoo, and J.O.Lee (2007).
Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran.
  Cell, 130, 906-917.
PDB codes: 2z62 2z63 2z64 2z65 2z66
17889640 I.Brodsky, and R.Medzhitov (2007).
Two modes of ligand recognition by TLRs.
  Cell, 130, 979-981.  
18026075 J.L.Strominger (2007).
Bacterial cell walls, innate immunity and immunoadjuvants.
  Nat Immunol, 8, 1269-1271.  
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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