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High resolution X-ray structures of mouse major urinary protein nasal isoform in complex with pheromones.

ABSTRACT: In mice, the major urinary proteins (MUP) play a key role in pheromonal communication by binding and transporting semiochemicals. MUP-IV is the only isoform known to be expressed in the vomeronasal mucosa. In comparison with the MUP isoforms that are abundantly excreted in the urine, MUP-IV is highly specific for the male mouse pheromone 2-sec-butyl-4,5-dihydrothiazole (SBT). To examine the structural basis of this ligand preference, we determined the X-ray crystal structure of MUP-IV bound to three mouse pheromones: SBT, 2,5-dimethylpyrazine, and 2-heptanone. We also obtained the structure of MUP-IV with 2-ethylhexanol bound in the cavity. These four structures show that relative to the major excreted MUP isoforms, three amino acid substitutions within the binding calyx impact ligand coordination. The F103 for A along with F54 for L result in a smaller cavity, potentially creating a more closely packed environment for the ligand. The E118 for G substitution introduces a charged group into a hydrophobic environment. The sidechain of E118 is observed to hydrogen bond to polar groups on all four ligands with nearly the same geometry as seen for the water-mediated hydrogen bond network in the MUP-I and MUP-II crystal structures. These differences in cavity size and interactions between the protein and ligand are likely to contribute to the observed specificity of MUP-IV.

SUBMITTER: Perez-Miller S

PROVIDER: S-EPMC2923500 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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High resolution X-ray structures of mouse major urinary protein nasal isoform in complex with pheromones.

Perez-Miller Samantha S Zou Qin Q Novotny Milos V MV Hurley Thomas D TD

Protein science : a publication of the Protein Society 20100801 8

In mice, the major urinary proteins (MUP) play a key role in pheromonal communication by binding and transporting semiochemicals. MUP-IV is the only isoform known to be expressed in the vomeronasal mucosa. In comparison with the MUP isoforms that are abundantly excreted in the urine, MUP-IV is highly specific for the male mouse pheromone 2-sec-butyl-4,5-dihydrothiazole (SBT). To examine the structural basis of this ligand preference, we determined the X-ray crystal structure of MUP-IV bound to t ...[more]

PMID: 20509168

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Project description:This paper presents the computer program D+ (https://scholars.huji.ac.il/uriraviv/book/d-0), where the reciprocal-grid (RG) algorithm is implemented. D+ efficiently computes, at high-resolution, the X-ray scattering curves from complex structures that are isotropically distributed in random orientations in solution. Structures are defined in hierarchical trees in which subunits can be represented by geometric or atomic models. Repeating subunits can be docked into their assembly symmetries, describing their locations and orientations in space. The scattering amplitude of the entire structure can be calculated by computing the amplitudes of the basic subunits on 3D reciprocal-space grids, moving up in the hierarchy, calculating the RGs of the larger structures, and repeating this process for all the leaves and nodes of the tree. For very large structures (containing over 100 protein subunits), a hybrid method can be used to avoid numerical artifacts. In the hybrid method, only grids of smaller subunits are summed and used as subunits in a direct computation of the scattering amplitude. D+ can accurately analyze both small- and wide-angle solution X-ray scattering data. This article describes how D+ applies the RG algorithm, accounts for rotations and translations of subunits, processes atomic models, accounts for the contribution of the solvent as well as the solvation layer of complex structures in a scalable manner, writes and accesses RGs, interpolates between grid points, computes numerical integrals, enables the use of scripts to define complicated structures, applies fitting algorithms, accounts for several coexisting uncorrelated populations, and accelerates computations using GPUs. D+ may also account for different X-ray energies to analyze anomalous solution X-ray scattering data. An accessory tool that can identify repeating subunits in a Protein Data Bank file of a complex structure is provided. The tool can compute the orientation and translation of repeating subunits needed for exploiting the advantages of the RG algorithm in D+. A Python wrapper (https://scholars.huji.ac.il/uriraviv/book/python-api) is also available, enabling more advanced computations and integration of D+ with other computational tools. Finally, a large number of tests are presented. The results of D+ are compared with those of other programs when possible, and the use of D+ to analyze solution scattering data from dynamic microtubule structures with different protofilament number is demonstrated. D+ and its source code are freely available for academic users and developers (https://bitbucket.org/uriraviv/public-dplus/src/master/).

Dataset Information

High resolution X-ray structures of mouse major urinary protein nasal isoform in complex with pheromones.

Publications

High resolution X-ray structures of mouse major urinary protein nasal isoform in complex with pheromones.

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