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PDBsum entry 1tlm
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protein ligands Protein-protein interface(s) links
Transport(thyroxine) PDB id
1tlm

 

 

 

 

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Contents
Protein chain
123 a.a. *
Ligands
MIL ×2
Waters ×130
* Residue conservation analysis
PDB id:
1tlm
Name: Transport(thyroxine)
Title: Structural aspects of inotropic bipyridine binding: crystal structure determination to 1.9 angstroms of the human serum transthyretin- milrinone complex
Structure: Transthyretin. Chain: a, b. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606
Biol. unit: Tetramer (from PQS)
Resolution:
1.90Å     R-factor:   0.173    
Authors: A.Wojtczak,J.Luft,V.Cody
Key ref: A.Wojtczak et al. (1993). Structural aspects of inotropic bipyridine binding. Crystal structure determination to 1.9 A of the human serum transthyretin-milrinone complex. J Biol Chem, 268, 6202-6206. PubMed id: 8454595
Date:
22-Dec-92     Release date:   31-Jan-94    
PROCHECK
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 Headers
 References

Protein chains
Pfam   ArchSchema ?
P02766  (TTHY_HUMAN) -  Transthyretin from Homo sapiens
Seq:
Struc: 		147 a.a.
123 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 Enzyme reactions 
   Enzyme class: E.C.?
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]

 

 
J Biol Chem 268:6202-6206 (1993)
PubMed id: 8454595  
 
 
Structural aspects of inotropic bipyridine binding. Crystal structure determination to 1.9 A of the human serum transthyretin-milrinone complex.
A.Wojtczak, J.R.Luft, V.Cody.
 
  ABSTRACT  
 
The crystal structure of human transthyretin (TTR) complexed with milrinone (2-methyl-5-cyano-3,4'-bipyridin-6(1H)-one), a positive inotropic cardiac agent, has been refined to R = 17.4% for 8-1.9-A resolution data. This report provides the first detailed description of protein interactions for an inotropic bipyridine agent which is an effective thyroid hormone binding competitor to transthyretin. Milrinone is bound along the 2-fold axis in the binding site with its substituted pyridone ring located deep within the channel of the two identical binding domains of the TTR tetramer. In this orientation the 5-cyano group occupies the same site as the 3'-iodine in the TTR complex with 3,3'-diiodothyronine (Wojtczak, A., Luft, J., and Cody, V. (1992) J. Biol. Chem. 267, 353-357), which is 3.5 A deeper in the channel than thyroxine (Blake, C. C. F., and Oately, S. J., (1977) Nature 268, 115-120). These structural results confirm computer modeling studies of milrinone structural homology with thyroxine and its TTR binding interactions and explain the effectiveness of milrinone competition for thyroxine binding to TTR. To understand the weaker binding affinity of the parent inotropic drug, amrinone (5-amino-3,4'-bipyridin-6(1H)-one), modeling studies of its TTR binding were carried out which indicate that the 5-amino group cannot participate in strong interactions with TTR and the lack of the 2-methyl further weakens amrinone binding.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
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.  
16204882 P.Neumann, V.Cody, and A.Wojtczak (2005).
Ligand binding at the transthyretin dimer-dimer interface: structure of the transthyretin-T4Ac complex at 2.2 Angstrom resolution.
  Acta Crystallogr D Biol Crystallogr, 61, 1313-1319.
PDB code: 1z7j
12553424 V.Cody (2002).
Mechanisms of molecular recognition: crystal structure analysis of human and rat transthyretin inhibitor complexes.
  Clin Chem Lab Med, 40, 1237-1243.  
11418763 A.Wojtczak, P.Neumann, and V.Cody (2001).
Structure of a new polymorphic monoclinic form of human transthyretin at 3 A resolution reveals a mixed complex between unliganded and T4-bound tetramers of TTR.
  Acta Crystallogr D Biol Crystallogr, 57, 957-967.
PDB code: 1ict
11468389 A.Wojtczak, V.Cody, J.R.Luft, and W.Pangborn (2001).
Structure of rat transthyretin (rTTR) complex with thyroxine at 2.5 A resolution: first non-biased insight into thyroxine binding reveals different hormone orientation in two binding sites.
  Acta Crystallogr D Biol Crystallogr, 57, 1061-1070.
PDB code: 1ie4
11058748 H.L.Monaco (2000).
The transthyretin-retinol-binding protein complex.
  Biochim Biophys Acta, 1482, 65-72.  
10957627 M.Ghosh, I.A.Meerts, A.Cook, A.Bergman, A.Brouwer, and L.N.Johnson (2000).
Structure of human transthyretin complexed with bromophenols: a new mode of binding.
  Acta Crystallogr D Biol Crystallogr, 56, 1085-1095.
PDB codes: 1e3f 1e4h 1e4z 1e5a
8536704 G.Zanotti, M.R.D'Acunto, G.Malpeli, C.Folli, and R.Berni (1995).
Crystal structure of the transthyretin--retinoic-acid complex.
  Eur J Biochem, 234, 563-569.
PDB code: 1tyr
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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