GeneFormatics 社

3次構造をベースにした蛋白質機能予測サービスのご紹介
株式会社 理経
バイオインフォマティクス販売推進室
小澤 幸弘

１．緒言

２．１ Novel Technology

近年では製薬会社や解析センターなどで Sequence データがGeneFormatics' Scientific Founders have developed

大量に産出されています。その中からいかに早く有用な Geneleading-edge technology that is based on the ideaを探し、創薬および特許に結び付けるかが重要になってきてthat the structures of protein functional sites areいます。今回ご紹介する GeneFormatics 社の「蛋白質機能予

three-dimensional,測サービス」は構造・機能予測の分野で世界的に権威ある Dr.

information is inherently limited to one dimension.

Jeffrey Skolnick 等により開発された Fuzzy Functional Form

Currently, techniques are available for makingという技術を用いて Sequence データの機能を予測し創薬開function predictions based solely on the one-

発、特許戦略の支援をする革新的なサービスです。最近のレdimensional

ポートによると Sequence のホモロジーが高くても機能は異な

methods produce inaccurate and incomplete results.

る、また機能は同じでもホモロジーは低いと行った報告が出Recognizing the limitations of these sequence-onlyています。今まで 1 次構造をベースに Sequence のホモロジ

techniques,ーから機能を予測していたのに対し、同社は 3 次構造をベー

GeneFormatics

スに機能予測するため少なく見積もって 10〜30%の精度の向Factory, which utilizes both the sequence and three-上を産出します。また１０００Sequence を一日に処理できるた

dimensional

め労力、コストそして期間を大幅に削減できます。

function. The Prediction Factory consists of two

while

sequencethehavegenetic

information,

sequence

but

these

ScientificFounders

developed

thestructural

information

atPrediction
topredictcomplementary processes: the Structure Prediction
Factory and the Function Prediction Factory.
２．２ Structure Prediction Factory
TheStructure

Prediction

Factory

uses

novel

techniques for determining a protein's threedimensional structure when only its sequence isknown. This predicted structure is inexact, but canbe created quickly without expending significant
computational resources. However, it is sufficiently
accurate for use in the Function Prediction Factoryfor determining the protein's functions and active
site residues.

1２．３ Function Prediction Factory
TheFunction

Prediction

detailed

Factoryfunctionalinformationfor

specific

uses

proprietary protein sequences. These multi-level,

GeneFormatics' proprietary Fuzzy Functional Form?

biologically relevant function annotations can aid intechnology to rapidly identify genomic sites oftarget recognition, significantly decreasing the timeinterest, allowing comparative analysis of sequences

required to develop a new product starting from thethat would otherwise not be recognized as being

gene protein sequence.

related.

Function Annotation Services provide our customers

Fuzzy Functional Forms are structural descriptors

with information about the likely functions of eachof the protein's functional sites. In the Function

sequence. Each sequence is annotated and the amino

Prediction Factory, Fuzzy Functional Forms areacid residues involved in activity and binding areapplied to the low resolution protein structures

explicitly identified. Models of the three-dimensional

created in the Structure Prediction Factory to findprotein structures for each protein sequence may

proteins with similar structural characteristics.

also be produced.

Protein function predictions made this way havebeen found to be much more accurate than those

３．２ Genome Analysis Services

resulting directly from protein sequence data. An

By far the most valuable method for sifting out

additional advantage is that the specific functional

proteins from genomic databases is the efficientsite is automatically identified in the protein's

prediction of protein function. At GeneFormatics, thestructure.

Scientific Founders have created the technology topredict the biological function of a protein from the

２．４ Remarkable ResultsIn

peer-reviewed

raw

publications,

GeneFormatics'sequence

data.

Unlikeothermethods,

GeneFormatics' Prediction Factory is not restricted

Prediction Factory Technology has been shown totomaking

predictions

achieve a conservatively estimated 10-30% higher

relationships between genes, and (unlike current

recognition rate of newly sequenced proteins overpublicly available tools) it is able to identify thecurrent sequence-based prediction methods. The

specific amino acid residues which are involved in

Scientific Founders have validated this approach by

the protein's functional activity.

correctly identifying all proteins that were already

GeneFormatics' solution is not genome specific, but

known to exhibit a given function for several

rather is applicable to any genome, whether human,genomes. More importantly, this technology has

plant, animal or microbial. Through Genome

made several correct predictions for novel proteins ofAnalysis Services, Geneformatics' technology can bepreviously unknown function, that could not beapplied quickly and easily to massive proprietary orpredicted using current methods.

publicgenome

based

sequenceonevolutionarydatabases.

Correct

identification of useful leads from this huge amount
３．１ Function Annotation Servicesof data allows our customers to concentrate their

GeneFormatics

research dollars on targets that have a highdelivers

comprehensive

bioinformatics-based services for the next level ofpotential for success.

proteomics research ? studying and understanding
thestructureandfunctionofproteins.

The

３．３ Model Building Services

Prediction Factory, developed in the laboratories of

GeneFormatics provides state-of-the-art analysis of

the company's Scientific Founders, can produce

proprietary sequences at significantly less cost than2

thatrequiredforsettingup

anin-house

numerous NIH study sections. He is an editorial

bioinformatics effort, and with significantly moreboard member of three different journals and is avaluable information than that which is generated

referee for 18 different peer-reviewed journals. Dr.

by other methods. Our Scientists and Staff have over

Skolnick has published over 200 research articles

25 years of combined experience in protein structureduring his scientific career and has received grants

prediction and in development, application, andfrom the NIH, NSF, the American Chemical Society,analysis of genomics and proteomics bioinformatics

and the Sloan Foundation.

tools.
We offer Model Building Services, which use ourJacquelyn Fetrow, Ph.D.

Structure Prediction Factory technology to provide

Chief Scientific Officer

our customers with approximate three-dimensional

Dr. Fetrow received her Ph.D. in biochemistry fromstructural models based on proprietary sequences.

the Pennsylvania State University in 1986. She

These inexact models are accurate enough to be used

received an NIH postdoctoral fellowship which she

to identify functional sites, but can be quickly

served at the University of Rochester Medical School

generated in large numbers to screen whole genomes.

and at MIT's Whitehead Institute for Biomedical

More detailed, exact models then need only beResearch. In 1990, she joined the faculty at theproduced for those proteins determined to be of

University at Albany in Albany, NY and wasfunctional interest. These detailed models, withpromoted to Associate Professor with tenure in 1995.

specific identification of active-site residues andIn 1998, she joined the faculty at The Scripps

geometrics, can then be used in the next step ofResearch Institute as an Associate Professor where

product development.

her research focused on protein structure andfunction

prediction.

In1999,shemovedto４．１ Scientific Founders

GeneFormatics as the Chief Scientific Officer. Dr.

Jeffrey Skolnick, Ph.D.

Fetrow is a member of eight professional societies, is

Director of Computational and Structural Biology,

an editorial board member for Proteins: Structure,

The Donald Danforth Plant Science Center

Function & Genetics, serves as a referee for eightDr. Skolnick received his Ph.D. in chemistry frompeer-reviewed journals, and has served on two NIH,

Yale University in 1978. He was a postdoctoral

one NSF, and one NASA study panels. She is thefellow at Bell Labs in 1979, and then joined theauthor of over 30 publications and has received

faculty at Louisiana State University as an

research grants from the NIH, NSF, and American

Assistant Professor. He moved to Washington

Chemical Society.

University in St. Louis in 1982 and was promoted to
Full Professor there in 1988. Dr. Skolnick was hired

Andrzej Kolinski, Ph.D.

as a Full Professor in Molecular Biology at The

Professor of Computational Genomics,The DonaldScripps Research Institute in 1989. In 1999, Dr.

Danforth Plant Science Center;

Skolnick was hired as the Director of Computational

Professor of Chemistry, University of Warsawand Structural Biology at The Donald DanforthDr. Kolinski received his Ph.D. in chemistry fromPlant Science Center in St. Louis. His research

the University of Warsaw in 1979. He has been on

focuses on protein structure analysis, structure

the faculty of the University of Warsaw since heprediction, and function prediction. He is a member

earned his doctorate, and is currently a Fullof two professional societies and has served on

Professor there. In 1989, Dr. Kolinski joined the3faculty at The Scripps Research Institute in La Jolla,

４．１

CA. In 1999, he was hired as a Full Professor at The

1.J. Skolnick, J.S. Fetrow: TIBTECH 18:34-39 (2000),

Donald Danforth Plant Science Center in St. Louis.

From genes to protein structure and function: Novel

Dr. Kolinski is also an International Scholar of theapplications of computational approaches in theHoward Hughes Medical Institute. He has won

genomic era.

several awards, including the Switoslawski Award

2. A. Kolinski, P. Rotkiewicz, B. Ilkowski, J. Skolnick:for the Best Science Done in 1984-1989 at theProteins

University of Warsaw. His research focuses onimprovement of threading-based protein models.

proteinof

3. J. Fetrow, N. Siew, J. Skolnick: FASEB Journal

biopolymeric systems. Dr. Kolinski is an author of(1999), Structure-based functional motif identifies aover 115 research publications.

potential disulfide oxidoreductase active site in thefoldingand

computersimulations

Reference

37:593-610(1999),

A

methodfor

theserine/threonine protein phosphatase-1 subfamily.

Adam Godzik, Ph.D.
Associate

4. Zhang, L., Godzik, A., Skolnick, J., and Fetrow, J.S.:

Professor,Program

Director,

FoldingandDesign

1998;3(6):535-48.

Functional

Bioinformatics and Biological Complexity, Theanalysis of E. coli proteins for members of theBurnham Institutealpha/beta hydrolase family.

Dr. Godzik received his Ph.D. in physics from the5.Fetrow, J.S., Godzik, A., and Skolnick, J.: J Mol Biol

University of Warsaw in 1990 and became a visiting

1998 Oct 2;282(4):703-711, Functional analysis of thescientist

Escherichia coli

attheEuropean

Molecular

Biologygenomeusing

Laboratories in 1990. Dr. Godzik then moved to The

structure-to-function

paradigm:

Scripps

proteinstheResearchInstitutewherehewasaexhibiting

thesequence-to-identification

ofglutaredoxin/thioredoxin

postdoctoral fellow from 1990 to 1992 and an

disulfide oxidoreductase activity.

Assistant Professor from 1992 until 1998. He then

6.Fetrow, J.S., and Skolnick, J.: J Mol Biol 1998 Sep

moved to the Burnham Institute as an Associate

4;281(5):949-68, Method for prediction of protein

Professor. In 1999 he became Program Director for

function

thestructure-to-function paradigm with application to

Bioinformatics

andBiologicalComplexity

program at the Burnham Institute. Dr. Godzik's

fromsequence

using

thesequence-to-glutaredoxins/thioredoxins and T1 ribonucleases.

research focuses on analysis of protein structure andfolding and on prediction of protein structure and7.L. Rychlewski, B. Zhang and A. Godzik: Proteinfunction. He is a member of two professional

Science 8:614-24 (1999), Functional insights fromsocieties and is referee for eight peer-reviewed

structural predictions: analysis of the Escherichia coli

journals. He is an author on over 40 research

genome.

publications. Dr. Godzik has received research

8.B. Zhang, L. Rychlewski, P. Pawlowski, J. Fetrow, J.

grants from the NIH and the NSF.

Skolnick and A. Godzik: Protein Science 8:1104-1115(1999), From fold predictions to function predictions:
Automation of functional site conservation analysis forfunctional genome predictions.

4