Three-dimensional crystal structure model of alpha1-AR subtype protein and establishment method thereof

A technology for crystal structure and method establishment, which can be used in chemical structure search, special data processing applications, instruments, etc., and can solve the problem that the three-dimensional protein crystal structure has not been obtained.

Active Publication Date: 2017-07-18
邹长林
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] alpha 1 -AR is an important member of the G protein-coupled receptor family, although its subtypes have been accurately distinguished from the sequence, but α 1 -The three-dimensional protein crystal structure of AR has not yet been obtained. In order to accurately study the structure-activity relationship between the target and the antagonist, it is necessary to establish a reasonable theoretical model

Method used

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  • Three-dimensional crystal structure model of alpha1-AR subtype protein and establishment method thereof
  • Three-dimensional crystal structure model of alpha1-AR subtype protein and establishment method thereof
  • Three-dimensional crystal structure model of alpha1-AR subtype protein and establishment method thereof

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Embodiment 1

[0032] This embodiment provides a 1 -A three-dimensional crystal structure model of the AR subtype protein and its establishment method, the establishment method comprising the following steps:

[0033] S1: with α 1 -AR isoform protein alpha 1A -AR,α 1B -AR and α 1D The amino acid sequence of -AR was used as a probe, and the protein crystal database was searched by the ProteinBlast program to obtain the homologous template protein β 2 -AR (Code: 2RH1);

[0034] Obtain three subtypes of α1 adrenoceptor (α1-AR) through swiss-prot (http: / / www.uniprot.org / ) 1A -AR, α 1B -AR, α 1D -AR) amino acid sequence, the swiss-prot sequence numbers are: P35348, P35368 and P25100 respectively. 2RH1 is a β2 adrenoceptor, which is a member of the GPCR receptor A family with the α1 adrenoceptor to be modeled ; and the β2 adrenergic receptor is an important template for studying GPCRs. It belongs to the same family of adrenoceptors as the α1 adrenoceptor to be modeled. It has higher scores...

Embodiment 2

[0043] This embodiment provides a 1 -Evaluation method of three-dimensional crystal structure model of AR subtype protein: using Procheck to obtain α obtained in Example 1 1A -AR,α 1B -AR and α 1D - The physiological and chemical parameters of the three-dimensional crystal structure model of AR are evaluated and analyzed, and the obtained Ramachandran plot can be used to illustrate the rotation degree of the bond between the α-carbon atom and the carbonyl carbon atom in the peptide bond in the protein or peptide stereostructure, and the α-carbon atom The rotation degree of the bond between the nitrogen atom and the nitrogen atom is mainly used to indicate the allowed and disallowed conformations of amino acids in proteins or peptides. More than 90% of the amino acids in the obtained Ramachandran plot are located in the core region, which conforms to the in vitro chemical energy rule.

[0044] The Procheck result of the present invention is as figure 2 , image 3 and Fi...

Embodiment 3

[0047] This embodiment obtains α according to embodiment one 1A -AR,α 1B -AR and α 1D -A 3D crystal structure model of AR, based on where the ubiquitous binding pocket of the GPCR is located, modeling α 1 -AR three subtypes α 1A -AR, α 1B -AR and α 1D - AR possible binding pockets and find α 1A -AR, α 1B -AR and α 1D - The key residues of the three subtypes of AR, the specific results are as follows Figure 8 , Figure 9 and Figure 10 shown.

[0048] alpha 1A – AR, α 1B -AR and α 1D -The key residues of the three subtypes of AR include: the amino acid residues at position 193 are Ile 193, Val 193 and Ile 193, the amino acid residues at position 293 are Met 293, Leu 293 and Leu 293, and the amino acid residues at position 302 are respectively The amino acids at positions are Lys302, Leu302 and Leu302, respectively. Although alpha 1 -The amino acid residues around the three subtypes of AR are very similar, but each subtype still has its own unique amino acid res...

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Abstract

The invention relates to a three-dimensional crystal structure model of alpha1-AR subtype protein and an establishment method thereof. The establishment method comprises the following steps of searching a protein crystal database with an amino acid sequence of the alpha1-AR subtype protein as a probe and obtaining a homologous template beta2-AR with the highest similarity through comparison with the amino acid sequence; utilizing a Prime module of (formula) to carry out homology modeling on the alpha1-AR subtype protein; and adopting an Macromodel module to optimize protein obtained by homology modeling and obtaining the three-dimensional crystal structure model of the alpha1-AR subtype protein through model evaluation. The invention provides model conformations of three alpha1-AR subtype proteins, namely alpha1A-AR, alpha1B-AR and alpha1D-AR and provides the basis for accurately researching structure-function relationship between a target spot and an antagonist; a possible binding packet is modelled, a key residue is found, and the theoretical basis is provided for explaining the selectivity of an alpha1-AR subtype selective antagonist.

Description

technical field [0001] The invention relates to the technical field of drug design, in particular to an α 1 - Three-dimensional crystal structure model of AR subtype protein and its establishment method. Background technique [0002] Benign prostatic hyperplasia (BPH) is characterized by prostatic hypertrophy and abnormal contraction of prostatic smooth muscle: on the one hand, the hypertrophy of the prostatic gland leads to compression of the urethra and obstruction of urinary flow in the bladder; 1 - Adrenergic receptors (adrenoceptors, ARs) affect bladder neck and prostate smooth muscle causing abnormal contraction. [0003] In the early days, inhibitors were used clinically to antagonize α 1 -AR, which reduces urethral pressure and increases urine flow rate in BPH patients, has been shown to be effective. Classical antagonists such as Prazosin, Terazosin, Doxazosin, and Alfuzosin have achieved good curative effect in the initial stage of treatment of BPH. However, du...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G06F19/00
CPCG16C20/40G16C20/50
Inventor 邹长林许芳孙宪强章慧陈文豪陈星星李慧芳
Owner 邹长林
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