PDBsum entry 1d2j

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protein metals links
Signaling protein PDB id
Protein chain
40 a.a. *
* Residue conservation analysis
PDB id:
Name: Signaling protein
Title: Ldl receptor ligand-binding module 6
Structure: Low-density lipoprotein receptor. Chain: a. Fragment: ligand-binding domain, sixth repeat. Synonym: lr6 . Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli bl21. Expression_system_taxid: 511693.
NMR struc: 20 models
Authors: C.L.North,S.C.Blacklow
Key ref:
C.L.North and S.C.Blacklow (2000). Solution structure of the sixth LDL-A module of the LDL receptor. Biochemistry, 39, 2564-2571. PubMed id: 10704205 DOI: 10.1021/bi992087a
23-Sep-99     Release date:   22-Mar-00    
Go to PROCHECK summary

Protein chain
Pfam   ArchSchema ?
P01130  (LDLR_HUMAN) -  Low-density lipoprotein receptor
860 a.a.
40 a.a.*
Key:    PfamA domain  PfamB domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)


DOI no: 10.1021/bi992087a Biochemistry 39:2564-2571 (2000)
PubMed id: 10704205  
Solution structure of the sixth LDL-A module of the LDL receptor.
C.L.North, S.C.Blacklow.
The low-density lipoprotein receptor (LDLR) is the primary mechanism for uptake of plasma cholesterol into cells and serves as a prototype for an entire class of cell surface receptors. The amino-terminal domain of the receptor consists of seven LDL-A modules; the third through the seventh modules all contribute to the binding of low-density lipoproteins (LDLs). Here, we present the NMR solution structure of the sixth LDL-A module (LR6) from the ligand binding domain of the LDLR. This module, which has little recognizable secondary structure, retains the essential structural features observed in the crystal structure of LDL-A module five (LR5) of the LDLR. Three disulfide bonds, a pair of buried residues forming a hydrophobic "mini-core", and a calcium-binding site that serves to organize the C-terminal lobe of the module all occupy positions in LR6 similar to those observed in LR5. The striking presence of a conserved patch of negative surface electrostatic potential among LDL-A modules of known structure suggests that ligand recognition by these repeats is likely to be mediated in part by electrostatic complementarity of receptor and ligand. Two variants of LR6, identified originally as familial hypercholesterolemia (FH) mutations, have been investigated for their ability to form native disulfide bonds under conditions that permit disulfide exchange. The first, E219K, lies near the amino-terminal end of LR6, whereas the second, D245E, alters one of the aspartate side chains that directly coordinate the bound calcium ion. After equilibration at physiologic calcium concentrations, neither E219K nor D245E folds to a unique disulfide isomer, indicating that FH mutations both within and distant from the calcium-binding site give rise to protein-folding defects.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20223219 C.J.Lee, A.De Biasio, and N.Beglova (2010).
Mode of interaction between beta2GPI and lipoprotein receptors suggests mutually exclusive binding of beta2GPI to the receptors and anionic phospholipids.
  Structure, 18, 366-376.
PDB code: 2kri
19676115 D.Beglov, C.J.Lee, A.De Biasio, D.Kozakov, R.Brenke, S.Vajda, and N.Beglova (2009).
Structural insights into recognition of beta2-glycoprotein I by the lipoprotein receptors.
  Proteins, 77, 940-949.  
19583244 Z.Zhao, and P.Michaely (2009).
The role of calcium in lipoprotein release by the low-density lipoprotein receptor.
  Biochemistry, 48, 7313-7324.  
  18626063 A.P.Lillis, L.B.Van Duyn, J.E.Murphy-Ullrich, and D.K.Strickland (2008).
LDL receptor-related protein 1: unique tissue-specific functions revealed by selective gene knockout studies.
  Physiol Rev, 88, 887-918.  
18331356 S.D.Roosendaal, J.Kerver, M.Schipper, K.W.Rodenburg, and D.J.Van der Horst (2008).
The complex of the insect LDL receptor homolog, lipophorin receptor, LpR, and its lipoprotein ligand does not dissociate under endosomal conditions.
  FEBS J, 275, 1751-1766.  
18343813 X.Arias-Moreno, J.L.Arolas, F.X.Aviles, J.Sancho, and S.Ventura (2008).
Scrambled isomers as key intermediates in the oxidative folding of ligand binding module 5 of the low density lipoprotein receptor.
  J Biol Chem, 283, 13627-13637.  
18677035 Z.Zhao, and P.Michaely (2008).
The epidermal growth factor homology domain of the LDL receptor drives lipoprotein release through an allosteric mechanism involving H190, H562, and H586.
  J Biol Chem, 283, 26528-26537.  
17245526 C.A.Wolf, F.Dancea, M.Shi, V.Bade-Noskova, H.Rüterjans, D.Kerjaschki, and C.Lücke (2007).
Solution structure of the twelfth cysteine-rich ligand-binding repeat in rat megalin.
  J Biomol NMR, 37, 321-328.
PDB code: 2i1p
17148455 E.J.Hopkins, S.Layfield, T.Ferraro, R.A.Bathgate, and P.R.Gooley (2007).
The NMR solution structure of the relaxin (RXFP1) receptor lipoprotein receptor class A module and identification of key residues in the N-terminal region of the module that mediate receptor activation.
  J Biol Chem, 282, 4172-4184.
PDB code: 2jm4
17044057 S.Cuesta-López, F.Falo, and J.Sancho (2007).
Computational diagnosis of protein conformational diseases: short molecular dynamics simulations reveal a fast unfolding of r-LDL mutants that cause familial hypercholesterolemia.
  Proteins, 66, 87-95.  
16769730 S.Contreras-Alcantara, J.A.Godby, and S.E.Delos (2006).
The single ligand-binding repeat of Tva, a low density lipoprotein receptor-related protein, contains two ligand-binding surfaces.
  J Biol Chem, 281, 22827-22838.  
16425180 W.Y.Kao, J.Qin, K.Fushitani, S.S.Smith, T.A.Gorr, C.K.Riggs, J.E.Knapp, B.T.Chait, and A.F.Riggs (2006).
Linker chains of the gigantic hemoglobin of the earthworm Lumbricus terrestris: primary structures of linkers L2, L3, and L4 and analysis of the connectivity of the disulfide bonds in linker L1.
  Proteins, 63, 174-187.  
16095885 D.V.Pastrana, A.J.Hanson, J.Knisely, G.Bu, and D.J.Fitzgerald (2005).
LRP 1 B functions as a receptor for Pseudomonas exotoxin.
  Biochim Biophys Acta, 1741, 234-239.  
15952897 H.Jeon, and S.C.Blacklow (2005).
Structure and physiologic function of the low-density lipoprotein receptor.
  Annu Rev Biochem, 74, 535-562.  
15950875 N.Beglova, and S.C.Blacklow (2005).
The LDL receptor: how acid pulls the trigger.
  Trends Biochem Sci, 30, 309-317.  
16282495 T.Rai, M.Caffrey, and L.Rong (2005).
Identification of two residues within the LDL-A module of Tva that dictate the altered receptor specificity of mutant subgroup A avian sarcoma and leukosis viruses.
  J Virol, 79, 14962-14966.  
  18516203 A.D.Marais (2004).
Familial hypercholesterolaemia.
  Clin Biochem Rev, 25, 49-68.  
15100232 E.J.Boswell, H.Jeon, S.C.Blacklow, and A.K.Downing (2004).
Global defects in the expression and function of the low density lipoprotein receptor (LDLR) associated with two familial hypercholesterolemia mutations resulting in misfolding of the LDLR epidermal growth factor-AB pair.
  J Biol Chem, 279, 30611-30621.  
15476573 M.L.Johnson, K.Harnish, R.Nusse, and W.Van Hul (2004).
LRP5 and Wnt signaling: a union made for bone.
  J Bone Miner Res, 19, 1749-1757.  
14694099 T.Rai, D.Marble, K.Rihani, and L.Rong (2004).
The spacing between cysteines two and three of the LDL-A module of Tva is important for subgroup A avian sarcoma and leukosis virus entry.
  J Virol, 78, 683-691.  
12429745 A.Li, M.Sadasivam, and J.L.Ding (2003).
Receptor-ligand interaction between vitellogenin receptor (VtgR) and vitellogenin (Vtg), implications on low density lipoprotein receptor and apolipoprotein B/E. The first three ligand-binding repeats of VtgR interact with the amino-terminal region of Vtg.
  J Biol Chem, 278, 2799-2806.  
14675545 G.Rudenko, and J.Deisenhofer (2003).
The low-density lipoprotein receptor: ligands, debates and lore.
  Curr Opin Struct Biol, 13, 683-689.  
12072496 M.Reithmayer, A.Reischl, L.Snyers, and D.Blaas (2002).
Species-specific receptor recognition by a minor-group human rhinovirus (HRV): HRV serotype 1A distinguishes between the murine and the human low-density lipoprotein receptor.
  J Virol, 76, 6957-6965.  
12381843 Q.Y.Wang, B.Manicassamy, X.Yu, K.Dolmer, P.G.Gettins, and L.Rong (2002).
Characterization of the LDL-A module mutants of Tva, the subgroup A Rous sarcoma virus receptor, and the implications in protein folding.
  Protein Sci, 11, 2596-2605.  
11861852 Q.Y.Wang, W.Huang, K.Dolmer, P.G.Gettins, and L.Rong (2002).
Solution structure of the viral receptor domain of Tva and its implications in viral entry.
  J Virol, 76, 2848-2856.
PDB code: 1jrf
12036962 V.Raussens, C.M.Slupsky, R.O.Ryan, and B.D.Sykes (2002).
NMR structure and dynamics of a receptor-active apolipoprotein E peptide.
  J Biol Chem, 277, 29172-29180.  
11258891 N.Beglova, C.L.North, and S.C.Blacklow (2001).
Backbone dynamics of a module pair from the ligand-binding domain of the LDL receptor.
  Biochemistry, 40, 2808-2815.  
11160709 Q.Y.Wang, K.Dolmer, W.Huang, P.G.Gettins, and L.Rong (2001).
Role of calcium in protein folding and function of Tva, the receptor of subgroup A avian sarcoma and leukosis virus.
  J Virol, 75, 2051-2058.  
11052664 C.L.North, and S.C.Blacklow (2000).
Evidence that familial hypercholesterolemia mutations of the LDL receptor cause limited local misfolding in an LDL-A module pair.
  Biochemistry, 39, 13127-13135.  
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.