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PDBsum entry 2qgb
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protein Protein-protein interface(s) links
Hormone/growth factor PDB id
2qgb

 

 

 

 

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Contents
Protein chain
115 a.a. *
Waters ×166
* Residue conservation analysis
PDB id:
2qgb
Name: Hormone/growth factor
Title: Human transthyretin (ttr) in apo-form
Structure: Transthyretin. Chain: a, b. Synonym: prealbumin, tbpa, ttr, attr. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ttr, palb. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.40Å     R-factor:   0.167     R-free:   0.188
Authors: S.Connelly,I.A.Wilson
Key ref: S.M.Johnson et al. (2008). Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors. J Med Chem, 51, 260-270. PubMed id: 18095641
Date:
28-Jun-07     Release date:   05-Feb-08    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P02766  (TTHY_HUMAN) -  Transthyretin from Homo sapiens
Seq:
Struc: 		147 a.a.
115 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 

 
J Med Chem 51:260-270 (2008)
PubMed id: 18095641  
 
 
Biochemical and structural evaluation of highly selective 2-arylbenzoxazole-based transthyretin amyloidogenesis inhibitors.
S.M.Johnson, S.Connelly, I.A.Wilson, J.W.Kelly.
 
  ABSTRACT  
 
To develop potent transthyretin (TTR) amyloidogenesis inhibitors that also display high binding selectivity in blood, it proves useful to systematically optimize each of the three substructural elements that comprise a typical inhibitor: the two aryl rings and the linker joining them. In the first study, described herein, structural modifications to one aryl ring were evaluated by screening a library of 2-arylbenzoxazoles bearing thyroid hormone-like aryl substituents on the 2-aryl ring. Several potent and highly selective amyloidogenesis inhibitors were identified that exhibit minimal thyroid hormone nuclear receptor and COX-1 binding. High resolution crystal structures (1.3-1.5 A) of three inhibitors (2f, 4f, and 4d) in complex with TTR were obtained to characterize their binding orientation. Collectively, the results demonstrate that thyroid hormone-like substitution patterns on one aryl ring lead to potent and highly selective TTR amyloidogenesis inhibitors that lack undesirable thyroid hormone receptor or COX-1 binding.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
20043671 S.Choi, N.Reixach, S.Connelly, S.M.Johnson, I.A.Wilson, and J.W.Kelly (2010).
A substructure combination strategy to create potent and selective transthyretin kinetic stabilizers that prevent amyloidogenesis and cytotoxicity.
  J Am Chem Soc, 132, 1359-1370.
PDB codes: 3imr 3ims 3imt 3imu 3imv 3imw
20133122 S.Connelly, S.Choi, S.M.Johnson, J.W.Kelly, and I.A.Wilson (2010).
Structure-based design of kinetic stabilizers that ameliorate the transthyretin amyloidoses.
  Curr Opin Struct Biol, 20, 54-62.  
18485534 S.D.Santos, R.Fernandes, and M.J.Saraiva (2010).
The heat shock response modulates transthyretin deposition in the peripheral and autonomic nervous systems.
  Neurobiol Aging, 31, 280-289.  
21059958 S.E.Kolstoe, P.P.Mangione, V.Bellotti, G.W.Taylor, G.A.Tennent, S.Deroo, A.J.Morrison, A.J.Cobb, A.Coyne, M.G.McCammon, T.D.Warner, J.Mitchell, R.Gill, M.D.Smith, S.V.Ley, C.V.Robinson, S.P.Wood, and M.B.Pepys (2010).
Trapping of palindromic ligands within native transthyretin prevents amyloid formation.
  Proc Natl Acad Sci U S A, 107, 20483-20488.
PDB codes: 3ipb 3ipe 3m1o
20028396 Y.Kawasaki, E.E.Chufan, V.Lafont, K.Hidaka, Y.Kiso, L.Mario Amzel, and E.Freire (2010).
How much binding affinity can be gained by filling a cavity?
  Chem Biol Drug Des, 75, 143-151.
PDB codes: 3kdb 3kdc 3kdd
19644733 J.N.Buxbaum, and N.Reixach (2009).
Transthyretin: the servant of many masters.
  Cell Mol Life Sci, 66, 3095-3101.  
19489721 J.W.Kozarich (2009).
The biochemistry of disease: desperately seeking syzygy.
  Annu Rev Biochem, 78, 55-63.  
19463001 P.K.Suryadevara, S.Olepu, J.W.Lockman, J.Ohkanda, M.Karimi, C.L.Verlinde, J.M.Kraus, J.Schoepe, W.C.Van Voorhis, A.D.Hamilton, F.S.Buckner, and M.H.Gelb (2009).
Structurally simple inhibitors of lanosterol 14alpha-demethylase are efficacious in a rodent model of acute Chagas disease.
  J Med Chem, 52, 3703-3715.  
19191553 S.M.Johnson, S.Connelly, I.A.Wilson, and J.W.Kelly (2009).
Toward optimization of the second aryl substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies.
  J Med Chem, 52, 1115-1125.
PDB codes: 3esn 3eso 3esp
19125186 T.Mairal, J.Nieto, M.Pinto, M.R.Almeida, L.Gales, A.Ballesteros, J.Barluenga, J.J.Pérez, J.T.Vázquez, N.B.Centeno, M.J.Saraiva, A.M.Damas, A.Planas, G.Arsequell, and G.Valencia (2009).
Iodine atoms: a new molecular feature for the design of potent transthyretin fibrillogenesis inhibitors.
  PLoS ONE, 4, e4124.
PDB codes: 3fc8 3fcb
18537267 A.R.Hurshman Babbes, E.T.Powers, and J.W.Kelly (2008).
Quantification of the thermodynamically linked quaternary and tertiary structural stabilities of transthyretin and its disease-associated variants: the relationship between stability and amyloidosis.
  Biochemistry, 47, 6969-6984.  
18811132 S.M.Johnson, S.Connelly, I.A.Wilson, and J.W.Kelly (2008).
Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies.
  J Med Chem, 51, 6348-6358.
PDB codes: 3cn0 3cn1 3cn2 3cn3 3cn4
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 codes are shown on the right.

 

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