Threaded Prion 3D Structures
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Introduction to threaded structures
Sequence resources (mouse nmr lengths)

Threaded 3DTemplate Sources
...install viewers

... human met 129
... human val 129

... sheep wildtype
... sheep Q171R
... sheep Q171H
... sheep R211Q

... bovine

... cat
... dog

... short inc. mouse
... mink
These structures are derived by threading the respective primary amino acid sequences onto refined mouse 1AG2 pdb coordinates 1AG2 at Swiss Model in the optimized mode of energy minimization, an online service developed by M. Peitsch.

It will shortly be possible thread vis-a-vis (unrefined) hamster coordinates, 2PRP. While this structure is close to mouse, the hamster structure seems to offer some advantages in the details of side-chain interactions, which is essential for interpreting alleles and mutations.

The levels of sequence homology are so high that the derived structures, based on experience with the threading technique, are probably quite reliable. Detailed hypotheses as to the structural roles of individual amino acids and the impacts of various mutations are speculative, but may prove to be robust through the ongoing cycle of structure refinement.

Threaded Prion 3D Structures

Introduction. The 3D structure of the prion molecule has been determined by solution nmr from two species, mouse and hamster. The mouse structure is shorter than hamster but has been through a process of refinement. Neither molecule is full length: the mouse fragment covers 124-226 beginning with GLGGY.. and ending in ....AYY. This structure is available from the Protein Database as accession 1AG2 [resp. Swiss Prot P04925]. The Syrian hamster structure, 2PRP, nominally extends from residues 90-231 but is useful only from 113-231. Refined hamster coordinates are expected by January, 1998.

Principles of threading. The tertiary structure of a protein is generally far more stable over evolutionary time than its primary structure (amino acid sequence). A process called 'threading' takes a known sequence of unknown tertiary structure and places it along a known structure of a homologous sequence. The fit is optimized for energy, lack of steric interference, optimized side-chain rotamer, and so on. The end result is essentially a prediction of the 3D structure of the unknown protein. If the two sequences differ at only one or two residues (polymorphisms and point mutations), the method is quite reliable. However, the accuracy falls off with decreasing homology, though useful results can sometimes be obtained with homology below 25%.

Online Resources. Swiss Model provides an excellent online threading service. Simply paste the target sequence and the reference pdb accession number in a window -- the pdb coordinates of the threaded structure are returned by email. The software requires an officially released reference pdb structure.

To compare and manually refine the two 3D structures, use Swiss-PdbViewer v 2.5 by Nicolas Guex & Manuel C. Peitsch. This amazing viewer has many advanced features allowing optimization of side chain rotamers, Ramachandran plots, and multiple alignments.

" Swiss-PdbViewer is an application that provides a user friendly interface allowing to analyse several proteins at the same time. The proteins can be superimposed in order to deduce structural alignments and compare their active sites or any other relevant parts. Amino acid mutations, H-bonds, angles and distances between atoms are easy to obtain.

Swiss-PdbViewer is tightly linked to Swiss-Model, an automated homology modelling server. Working with these two programs greatly reduces the amount of work necessary to generate homology models, as it is possible to thread a protein primary sequence onto a 3D template and get an immediate feedback of how well the threaded protein will be accepted by the reference structure before submitting a request to build missing loops and refine sidechain packing. Finally, stunning ray-traced quality scenes can be generated using POV-Ray."

>Mus_long_L140F_V234T
GLGGYMLGSAMSRPMIHFGNDWEDRYYRENMYRYPNQVYYRPVDQYSNQNNFVHDCVNITIKQHTVVTTTKGENFTETDVKMMERVVEQMCVTQYQKESQAYY

>Mus_short
GLGGYMLGSAMSRPMIHLGNDWEDRYYRENMYRYPNQVYYRPVDQYSNQNNFVHDCVNITIKQHTVVTTTKGENFTETDVKMMERVVEQMCVTQYQKESQAYY

>hamster_Syrian
GLGGYMLGSAMSRPMMHFGNDWEDRYYRENMNRYPNQVYYRPVDQYNNQNNFVHDCVNITIKQHTVTTTTKGENFTETDIKIMERVVEQMCTTQYQKESQAYYD

>homo_sap_human_wt
GLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYY

>homo_sap_human_M129V
GLGGYVLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYY

>homo_sap_human_N171S
GLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYY

>homo_sap_human_D178N
GLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYY

>homo_sap_human_V180I
GLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYY

>homo_sap_human_T183A
GLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYY

>homo_sap_human_F198S
GLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYY

>homo_sap_human_E200K
GLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYY

>homo_sap_human_R208H
GLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMEHVVEQMCITQYERESQAYY

>homo_sap_human_V210I 
GLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYY

>homo_sap_human_Q217R
GLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYY

>homo_sap_human_E219K
GLGGYMLGSAMSRPIIHFGSDYEDRYYRENMHRYPNQVYYRPMDEYSNQNNFVHDCVNITIKQHTVTTTTKGENFTETDVKMMERVVEQMCITQYERESQAYY

>bossers_SHPRP_wt
GLGGYMLGSAMSRPLIHFGNDYEDRYYRENMYRYPNQVYYRPVDQYSNQNNFVHDCVNITVKQHTVTTTTKGENFTETDIKIMERVVEQMCITQYQRESQAYY

>bossers_SSHPRP_A136V A133 hamster
GLGGYMLGSVMSRPLIHFGNDYEDRYYRENMYRYPNQVYYRPVDQYSNQNNFVHDCVNITVKQHTVTTTTKGENFTETDIKIMERVVEQMCITQYQRESQAYY

>bossers_SHPRP_M137T M134 hamster
GLGGYMLGSATSRPLIHFGNDYEDRYYRENMYRYPNQVYYRPVDQYSNQNNFVHDCVNITVKQHTVTTTTKGENFTETDIKIMERVVEQMCITQYQRESQAYY

>bossers_SHPRP_L141F  MMHF138 hamster GLGGYMLGSAMSRPFIHFGNDYEDRYYRENMYRYPNQVYYRPVDQYSNQNNFVHDCVNITVKQHTVTTTTKGENFTETDIKIMERVVEQMCITQYQRESQAYY

>bossers_SHPRP_R154H  R151 hamster
GLGGYMLGSAMSRPLIHFGNDYEDRYYHENMYRYPNQVYYRPVDQYSNQNNFVHDCVNITVKQHTVTTTTKGENFTETDIKIMERVVEQMCITQYQRESQAYY

>bossers_SHPRP_Q171R  Q168 hamster
GLGGYMLGSAMSRPLIHFGNDYEDRYYRENMYRYPNQVYYRPVDRYSNQNNFVHDCVNITVKQHTVTTTTKGENFTETDIKIMERVVEQMCITQYQRESQAYY

>bossers_SHPRP_Q171H  Q168 hamster
GLGGYMLGSAMSRPLIHFGNDYEDRYYRENMYRYPNQVYYRPVDHYSNQNNFVHDCVNITVKQHTVTTTTKGENFTETDIKIMERVVEQMCITQYQRESQAYY

>bossers_SHPRP_R211Q  R208 hamster
GLGGYMLGSAMSRPLIHFGNDYEDRYYRENMYRYPNQVYYRPVDQYSNQNNFVHDCVNITVKQHTVTTTTKGENFTETDIKIMEQVVEQMCITQYQRESQAYY

>Bovine_short
GLGGYMLGSAMSRPLIHFGSDYEDRYYRENMHRYPNQVYYRPVDQYSNQNNFVHDCVNITVKEHTVTTTTKGENFTETDIKMMKRVVEQMCITQYQRESQAYY

>cat_lpool
GLGGYMLGSAMSRPLIHFGNDYEDRYYRENMYRYPDQVYYRPVDQYSNQNNFVRDCVNITVKQRTVTTTTKGENFTETDMKIMERVVEQMCVTQYQKESEAYY
  
>mink_muvi
GLGGYMLGSAMSRPLIHFGNDYEDRYYRENMYRYPNQVYYKPVDQYSNQNNFVHDCVNITVKQHTVTTTTKGENFTETDMKIMERVVEQMCVTQYQRESEAYY

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