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High-resolution crystal structures of two crystal forms of human cyclophilin D in complex with PEG 400 molecules.

ABSTRACT: Cyclophilin D (CypD) is a key mitochondrial target for amyloid-?-induced mitochondrial and synaptic dysfunction and is considered a potential drug target for Alzheimer's disease. The high-resolution crystal structures of primitive orthorhombic (CypD-o) and primitive tetragonal (CypD-t) forms have been determined to 1.45 and 0.85?Å resolution, respectively, and are nearly identical structurally. Although an isomorphous structure of CypD-t has previously been reported, the structure reported here was determined at atomic resolution, while CypD-o represents a new crystal form for this protein. In addition, each crystal form contains a PEG 400 molecule bound to the same region along with a second PEG 400 site in CypD-t which occupies the cyclosporine A inhibitor binding site of CypD. Highly precise structural information for CypD should be extremely useful for discerning the detailed interaction of small molecules, particularly drugs and/or inhibitors, bound to CypD. The 0.85?Å resolution structure of CypD-t is the highest to date for any CypD structure.

SUBMITTER: Valasani KR

PROVIDER: S-EPMC4051522 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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High-resolution crystal structures of two crystal forms of human cyclophilin D in complex with PEG 400 molecules.

Valasani Koteswara Rao KR Carlson Emily A EA Battaile Kevin P KP Bisson Andrea A Wang Chunyu C Lovell Scott S ShiDu Yan Shirley S

Acta crystallographica. Section F, Structural biology communications 20140524 Pt 6

Cyclophilin D (CypD) is a key mitochondrial target for amyloid-β-induced mitochondrial and synaptic dysfunction and is considered a potential drug target for Alzheimer's disease. The high-resolution crystal structures of primitive orthorhombic (CypD-o) and primitive tetragonal (CypD-t) forms have been determined to 1.45 and 0.85 Å resolution, respectively, and are nearly identical structurally. Although an isomorphous structure of CypD-t has previously been reported, the structure reported here ...[more]

PMID: 24915078

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Project description:The crystal structure of a commercially available form of human recombinant (HR) insulin, Insugen (I), used in the treatment of diabetes has been determined to 0.92 Å resolution using low temperature, 100 K, synchrotron X-ray data collected at 16,000 keV (? = 0.77 Å). Refinement carried out with anisotropic displacement parameters, removal of main-chain stereochemical restraints, inclusion of H atoms in calculated positions, and 220 water molecules, converged to a final value of R = 0.1112 and Rfree = 0.1466. The structure includes what is thought to be an ordered propanol molecule (POL) only in chain D(4) and a solvated acetate molecule (ACT) coordinated to the Zn atom only in chain B(2). Possible origins and consequences of the propanol and acetate molecules are discussed. Three types of amino acid representation in the electron density are examined in detail: (i) sharp with very clearly resolved features; (ii) well resolved but clearly divided into two conformations which are well behaved in the refinement, both having high quality geometry; (iii) poor density and difficult or impossible to model. An example of type (ii) is observed for the intra-chain disulphide bridge in chain C(3) between S?6-S?11 which has two clear conformations with relative refined occupancies of 0.8 and 0.2, respectively. In contrast the corresponding S-S bridge in chain A(1) shows one clearly defined conformation. A molecular dynamics study has provided a rational explanation of this difference between chains A and C. More generally, differences in the electron density features between corresponding residues in chains A and C and chains B and D is a common observation in the Insugen (I) structure and these effects are discussed in detail. The crystal structure, also at 0.92 Å and 100 K, of a second commercially available form of human recombinant insulin, Intergen (II), deposited in the Protein Data Bank as 3W7Y which remains otherwise unpublished is compared here with the Insugen (I) structure. In the Intergen (II) structure there is no solvated propanol or acetate molecule. The electron density of Intergen (II), however, does also exhibit the three types of amino acid representations as in Insugen (I). These effects do not necessarily correspond between chains A and C or chains B and D in Intergen (II), or between corresponding residues in Insugen (I). The results of this comparison are reported. Graphical abstract Conformations of PheB25 and PheD25 in three insulin structures: implications for biological activity? Insulin residues PheB25 and PheD25 are considered to be important for insulin receptor binding and changes in biological activity occur when these residues are modified. In porcine insulin and Intergen (II) PheB25 adopts conformation B and PheD25 conformation D. However, unexpectedly PheB25 in Insugen (I) human recombinant insulin adopts two distinct conformations corresponding to B and D, Figure 1 and PheD25 adopts a single conformation corresponding to B not D, Figure 2. Conformations of this residue in the ultra-high resolution structure of Insugen (I) are therefore unique within this set. Figures were produced with Biovia, Discovery Studio 2016.

Dataset Information

High-resolution crystal structures of two crystal forms of human cyclophilin D in complex with PEG 400 molecules.

Publications

High-resolution crystal structures of two crystal forms of human cyclophilin D in complex with PEG 400 molecules.

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