PDBsum entry 4drh

Isomerase/transferase

PDB id: 4drh

Contents

Protein chains

132 a.a.

95 a.a.

89 a.a.

Ligands

RAP ×2

SO4 ×21

Waters ×89

PDB id:

4drh

Name:

Isomerase/transferase

Title:

Co-crystal structure of the ppiase domain of fkbp51, rapamycin and the frb fragment of mtor at low ph

Structure:

Peptidyl-prolyl cis-trans isomerase fkbp5. Chain: a, d. Fragment: fkbp51 fk1 domain, unp residues 1-140. Synonym: ppiase fkbp5, 51 kda fk506-binding protein, 51 kda fkbp, fkbp-51, 54 kda progesterone receptor-associated immunophilin, androgen-regulated protein 6, ff1 antigen, fk506-binding protein 5, fkbp-5, fkbp54, p54, hsp90-binding immunophilin, rotamase. Engineered: yes. Serine/threonine-protein kinase mtor.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: aig6, fkbp5, fkbp51. Expressed in: escherichia coli. Expression_system_taxid: 469008. Gene: frap, frap1, frap2, mtor, raft1, rapt1.

Resolution:

2.30Å R-factor: 0.189 R-free: 0.226

Authors:

A.M.Maerz,A.Bracher,F.Hausch

Key ref:

A.M.März et al. (2013). Large FK506-binding proteins shape the pharmacology of rapamycin. Mol Cell Biol, 33, 1357-1367. PubMed id: 23358420 DOI: 10.1128/MCB.00678-12

Date:

17-Feb-12 Release date: 06-Feb-13

Protein chains

Q13451  (FKBP5_HUMAN) -  Peptidyl-prolyl cis-trans isomerase FKBP5 from Homo sapiens

Seq: 457 a.a.

Struc: 132 a.a.

Protein chain

P42345  (MTOR_HUMAN) -  Serine/threonine-protein kinase mTOR from Homo sapiens

Seq: 2549 a.a.

Struc: 95 a.a.*

Protein chain

P42345  (MTOR_HUMAN) -  Serine/threonine-protein kinase mTOR from Homo sapiens

Seq: 2549 a.a.

Struc: 89 a.a.*

* PDB and UniProt seqs differ at 13 residue positions (black crosses)

Enzyme reactions

• Enzyme class 2: Chains A, D: E.C.5.2.1.8 - peptidylprolyl isomerase.
• Reaction: [protein]-peptidylproline (omega=180) = [protein]-peptidylproline (omega=0)
• Enzyme class 3: Chains B, E: E.C.2.7.10.2 - non-specific protein-tyrosine kinase.
• Reaction: L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H⁺
• Enzyme class 4: Chains B, E: E.C.2.7.11.1 - non-specific serine/threonine protein kinase.
• Reaction:
  1. L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H⁺
  2. L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H⁺

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1128/MCB.00678-12

Mol Cell Biol 33:1357-1367 (2013)

PubMed id: 23358420

Large FK506-binding proteins shape the pharmacology of rapamycin.

A.M.März, A.K.Fabian, C.Kozany, A.Bracher, F.Hausch.

ABSTRACT

The immunosuppressant and anticancer drug rapamycin works by inducing inhibitory protein complexes with the kinase mTOR, an important regulator of growth and proliferation. The obligatory accessory partner of rapamycin is believed to be FK506-binding protein 12 (FKBP12). Here we show that rapamycin complexes of larger FKBP family members can tightly bind to mTOR and potently inhibit its kinase activity. Cocrystal structures with FKBP51 and FKBP52 reveal the modified molecular binding mode of these alternative ternary complexes in detail. In cellular model systems, FKBP12 can be functionally replaced by larger FKBPs. When the rapamycin dosage is limiting, mTOR inhibition of S6K phosphorylation can be enhanced by FKBP51 overexpression in mammalian cells, whereas FKBP12 is dispensable. FKBP51 could also enable the rapamycin-induced hyperphosphorylation of Akt, which depended on higher FKBP levels than rapamycin-induced inhibition of S6K phosphorylation. These insights provide a mechanistic rationale for preferential mTOR inhibition in specific cell or tissue types by engaging specific FKBP homologs.