GTPase KRas: Difference between revisions

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<StructureSection load='4ept' size='350' side='right' caption='Structure of human GDP-bound GTPase KRas G12 mutant complex with inhibitor and GDP (PDB entry [[4ept]])' scene=''>
<StructureSection load='' size='400' side='right' caption='Structure of human GDP-bound GTPase KRas G12 mutant complex with inhibitor and GDP (PDB entry [[4ept]])' scene='78/781207/Cv/1'>
== Function ==
== Function ==


Line 15: Line 15:
== Structural highlights ==
== Structural highlights ==


The GDP-bound KRas binds a small molecule inhibitor in its binding cleft following conformational change of the protein<ref>PMID:22566140</ref>.
The GDP-bound KRas binds a <scene name='78/781207/Cv/2'>small molecule inhibitor in its binding cleft</scene> following conformational change of the protein<ref>PMID:22566140</ref>. Water molecules are shown as red spheres.
</StructureSection>
*<scene name='78/781207/Cv/9'>Inhibitor binding cleft</scene>.
*<scene name='78/781207/Cv/7'>GDP binding site</scene>.
*<scene name='78/781207/Cv/8'>Mg coordination site</scene>.
*<scene name='78/781207/Cv/10'>GDP/Mg binding cleft</scene>.
 
== 3D Structures of GTPase KRas ==
== 3D Structures of GTPase KRas ==
[[GTPase KRas 3D structures]]


Updated on {{REVISIONDAY2}}-{{MONTHNAME|{{REVISIONMONTH}}}}-{{REVISIONYEAR}}
</StructureSection>
{{#tree:id=OrganizedByTopic|openlevels=0|
 
*GTPase KRas
 
**[[5uk9]] – hKRas + GCP + GDP – human <br />
**[[5vq2]] – hKRas + GTP <br />
**[[5w22]], [[4obe]], [[4lpk]], [[5vq8]] – hKRas + GDP <br />
**[[3gft]] – hKRas (mutant) + GTP analog <br />
**[[4l8g]], [[4ldj]], [[4ql3]], [[4tq9]], [[4tqa]], [[6asa]], [[6ase]], [[5whd]], [[5uqw]], [[5us4]], [[5vp7]], [[5vq0]], [[5vq1]], [[4wa7]], [[4lrw]] – hKRas (mutant) + GDP  <br />
**[[5vpi]], [[5vpz]], [[5vq6]] – hKRas (mutant) + GTP  <br />
**[[5usj]], [[5vpy]] – hKRas (mutant) + GNP  <br />
**[[6bp1]], [[4dsn]] – hKRas (mutant) + GCP  <br />
**[[4dso]] – hKRas (mutant) + inhibitor + GSP  <br />
**[[4dst]] – hKRas (mutant) + inhibitor + GCP  <br />
**[[5kyk]] – hKRas + inhibitor <br />
**[[4nmm]] – hKRas (mutant) + inhibitor <br />
**[[5v9o]], [[5f2e]], [[5v9u]], [[4dsu]], [[4luc]], [[4lv6]], [[4lyf]], [[4lyh]], [[4lyj]], [[4m1o]], [[4m1s]], [[4m1t]], [[4m1w]], [[4m1y]], [[4m21]], [[4m22]], [[4epr]], [[4ept]], [[4epv]], [[4epw]], [[4epx]], [[4epy]], [[4q02]], [[4q03]], [[5vbm]], [[5v6s]], [[5v6v]], [[6ark]], [[5xco]] – hKRas (mutant) + GDP + inhibitor <br />
**[[5vbz]] – hKRas (mutant) + GNP + inhibitor <br />
**[[5v71]], [[5v9l]] – hKRas (mutant) + GDP + quinazoline inhibitor <br />
 
*GTPase KRas complex with protein
 
**[[5wha]], [[5whb]] – hKRas (mutant) + miniprotein + GDP  <br />
**[[5wpl]], [[5whe]], [[5wpm]], [[5wlb]] – hKRas (mutant) + miniprotein + GNP  <br />
**[[5o2s]], [[5mlb]] – hKRas + darpin K27 + GDP  <br />
**[[5o2s]], [[5tb5]] – hKRas + GMP-PDE d + farnesyl + GDP  <br />
**[[5o2t]], [[5mla]] – hKRas + darpin 55 + GSP  <br />
**[[5o2s]] – hKRas + R11.1.6 + GNP  <br />
**[[5ufq]] – hKRas (mutant) + R11.1.6 + GNP  <br />
**[[2msc]], [[2msd]] – hKRas + apolipoprotein + GDP - NMR<br />
**[[2mse]] – hKRas + apolipoprotein + A-Raf + GDP - NMR<br />
}}


== References ==
== References ==
<references/>
<references/>
[[Category:Topic Page]]
[[Category:Topic Page]]

Latest revision as of 10:31, 21 July 2019

Function

GTPase KRas (KRas) plays a critical role in the control of cellular growth. Kras stands for Kirsten rat sarcoma virus gene. KRas is a small GTPase that functions as molecular switches by alternating

between inactive GDP-bound state and active GTP-bound state[1].

Disease

A single mutation of KRas G12C activates KRas and is implicated with various malignancies including lung adenocarcinoma, mutinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma[2]. KRas mutations are the most common genetic abnormalities in cancer.

Relevance

KRas inhibition represents an attractive therapeutic strategy for many cancers.

Structural highlights

The GDP-bound KRas binds a following conformational change of the protein[3]. Water molecules are shown as red spheres.

  • .
  • .
  • .
  • .

3D Structures of GTPase KRas

GTPase KRas 3D structures


Structure of human GDP-bound GTPase KRas G12 mutant complex with inhibitor and GDP (PDB entry 4ept)

Drag the structure with the mouse to rotate

ReferencesReferences

  1. ↑ Milburn MV, Tong L, deVos AM, Brunger A, Yamaizumi Z, Nishimura S, Kim SH. Molecular switch for signal transduction: structural differences between active and inactive forms of protooncogenic ras proteins. Science. 1990 Feb 23;247(4945):939-45. PMID:2406906
  2. ↑ Shibata H, Ohike N, Norose T, Isobe T, Suzuki R, Imai H, Shiokawa A, Aoki T, Murakami M, Mizukami H, Tanaka JI, Takimoto M. Mucinous Cystic Neoplasms Lined by Abundant Mucinous Epithelium Frequently Involve KRAS Mutations and Malignant Progression. Anticancer Res. 2017 Dec;37(12):7063-7068. doi: 10.21873/anticanres.12178. PMID:29187496 doi:http://dx.doi.org/10.21873/anticanres.12178
  3. ↑ Sun Q, Burke JP, Phan J, Burns MC, Olejniczak ET, Waterson AG, Lee T, Rossanese OW, Fesik SW. Discovery of Small Molecules that Bind to K-Ras and Inhibit Sos-Mediated Activation. Angew Chem Int Ed Engl. 2012 May 8. doi: 10.1002/anie.201201358. PMID:22566140 doi:10.1002/anie.201201358

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Michal Harel, Alexander Berchansky, Joel L. Sussman
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